WO2019006384A1 - Traitement des anévrismes - Google Patents
Traitement des anévrismes Download PDFInfo
- Publication number
- WO2019006384A1 WO2019006384A1 PCT/US2018/040422 US2018040422W WO2019006384A1 WO 2019006384 A1 WO2019006384 A1 WO 2019006384A1 US 2018040422 W US2018040422 W US 2018040422W WO 2019006384 A1 WO2019006384 A1 WO 2019006384A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- subject
- inhibitor
- aneurysm
- haa
- administered
- Prior art date
Links
- 206010002329 Aneurysm Diseases 0.000 title claims abstract description 350
- 238000011282 treatment Methods 0.000 title description 24
- WJXSWCUQABXPFS-UHFFFAOYSA-N 3-hydroxyanthranilic acid Chemical compound NC1=C(O)C=CC=C1C(O)=O WJXSWCUQABXPFS-UHFFFAOYSA-N 0.000 claims abstract description 345
- 238000000034 method Methods 0.000 claims abstract description 217
- 108010031676 Kynureninase Proteins 0.000 claims abstract description 204
- 102000005447 kynureninase Human genes 0.000 claims abstract description 204
- 208000002223 abdominal aortic aneurysm Diseases 0.000 claims abstract description 182
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 claims abstract description 170
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 67
- 230000037361 pathway Effects 0.000 claims abstract description 59
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003112 inhibitor Substances 0.000 claims description 661
- 208000007474 aortic aneurysm Diseases 0.000 claims description 306
- 102100037652 Kynurenine 3-monooxygenase Human genes 0.000 claims description 176
- 108010033242 Kynurenine 3-monooxygenase Proteins 0.000 claims description 176
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 claims description 146
- 229960003526 acipimox Drugs 0.000 claims description 143
- 201000008982 Thoracic Aortic Aneurysm Diseases 0.000 claims description 132
- 208000003457 familial thoracic 1 aortic aneurysm Diseases 0.000 claims description 123
- 201000008450 Intracranial aneurysm Diseases 0.000 claims description 106
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 82
- 208000035475 disorder Diseases 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 63
- 230000035772 mutation Effects 0.000 claims description 56
- 238000002224 dissection Methods 0.000 claims description 47
- 239000005541 ACE inhibitor Substances 0.000 claims description 42
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims description 42
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims description 42
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 42
- 210000002966 serum Anatomy 0.000 claims description 38
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 36
- 238000011161 development Methods 0.000 claims description 35
- 230000003187 abdominal effect Effects 0.000 claims description 26
- 229960004799 tryptophan Drugs 0.000 claims description 26
- 230000008439 repair process Effects 0.000 claims description 25
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 24
- 229960003722 doxycycline Drugs 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 239000002876 beta blocker Substances 0.000 claims description 23
- 229940097320 beta blocking agent Drugs 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 208000001826 Marfan syndrome Diseases 0.000 claims description 21
- 230000002401 inhibitory effect Effects 0.000 claims description 21
- 108010072768 3-hydroxyanthranilate 3,4-dioxygenase Proteins 0.000 claims description 20
- 230000012010 growth Effects 0.000 claims description 20
- 208000011580 syndromic disease Diseases 0.000 claims description 20
- 102100029016 3-hydroxyanthranilate 3,4-dioxygenase Human genes 0.000 claims description 19
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 19
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims description 18
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 18
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 claims description 18
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 18
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 18
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 18
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 18
- 208000002251 Dissecting Aneurysm Diseases 0.000 claims description 18
- 239000012824 ERK inhibitor Substances 0.000 claims description 18
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 18
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 18
- 239000004098 Tetracycline Substances 0.000 claims description 18
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 18
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 18
- 229960002274 atenolol Drugs 0.000 claims description 18
- 229960002568 ethinylestradiol Drugs 0.000 claims description 18
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims description 18
- 229960002297 fenofibrate Drugs 0.000 claims description 18
- 229960004773 losartan Drugs 0.000 claims description 18
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 18
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 18
- 229960000619 nebivolol Drugs 0.000 claims description 18
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 claims description 18
- 229960002582 perindopril Drugs 0.000 claims description 18
- 229960002965 pravastatin Drugs 0.000 claims description 18
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 18
- 229960005224 roxithromycin Drugs 0.000 claims description 18
- 238000009097 single-agent therapy Methods 0.000 claims description 18
- 229960005187 telmisartan Drugs 0.000 claims description 18
- 229960002180 tetracycline Drugs 0.000 claims description 18
- 229930101283 tetracycline Natural products 0.000 claims description 18
- 235000019364 tetracycline Nutrition 0.000 claims description 18
- 229960001722 verapamil Drugs 0.000 claims description 18
- 150000003522 tetracyclines Chemical class 0.000 claims description 17
- 206010002895 aortic dissection Diseases 0.000 claims description 16
- 238000011477 surgical intervention Methods 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- ZADWXFSZEAPBJS-SNVBAGLBSA-N (2r)-2-amino-3-(1-methylindol-3-yl)propanoic acid Chemical compound C1=CC=C2N(C)C=C(C[C@@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-SNVBAGLBSA-N 0.000 claims description 14
- 208000002197 Ehlers-Danlos syndrome Diseases 0.000 claims description 14
- YGACXVRLDHEXKY-WXRXAMBDSA-N O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 Chemical compound O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 YGACXVRLDHEXKY-WXRXAMBDSA-N 0.000 claims description 14
- 210000002381 plasma Anatomy 0.000 claims description 14
- ZBRKMOHDGFGXLN-BQBZGAKWSA-N (1s,2s)-2-(3,4-dichlorobenzoyl)cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H]1C(=O)C1=CC=C(Cl)C(Cl)=C1 ZBRKMOHDGFGXLN-BQBZGAKWSA-N 0.000 claims description 13
- YPBKTZBXSBLTDK-PKNBQFBNSA-N (3e)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole Chemical compound NS(=O)(=O)NCCNC1=NON\C1=C(N=O)/NC1=CC=C(F)C(Br)=C1 YPBKTZBXSBLTDK-PKNBQFBNSA-N 0.000 claims description 13
- 201000005978 Loeys-Dietz syndrome Diseases 0.000 claims description 13
- NDPBMCKQJOZAQX-UHFFFAOYSA-N Ro 61-8048 Chemical compound C1=C(OC)C(OC)=CC=C1S(=O)(=O)NC1=NC(C=2C=C(C=CC=2)[N+]([O-])=O)=CS1 NDPBMCKQJOZAQX-UHFFFAOYSA-N 0.000 claims description 13
- 210000001367 artery Anatomy 0.000 claims description 13
- 238000002059 diagnostic imaging Methods 0.000 claims description 13
- 229950006370 epacadostat Drugs 0.000 claims description 13
- 229950007250 navoximod Drugs 0.000 claims description 13
- TXUWMXQFNYDOEZ-UHFFFAOYSA-N 5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylidene-4-imidazolidinone Chemical compound O=C1N(C)C(=S)NC1CC1=CNC2=CC=CC=C12 TXUWMXQFNYDOEZ-UHFFFAOYSA-N 0.000 claims description 12
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 12
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims description 12
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims description 12
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 12
- 229960000911 benserazide Drugs 0.000 claims description 12
- 239000000480 calcium channel blocker Substances 0.000 claims description 12
- KRTIYQIPSAGSBP-KLAILNCOSA-N linrodostat Chemical compound C1(CCC(CC1)C1=C2C=C(F)C=CC2=NC=C1)[C@@H](C)C(=O)NC1=CC=C(Cl)C=C1 KRTIYQIPSAGSBP-KLAILNCOSA-N 0.000 claims description 12
- 238000012216 screening Methods 0.000 claims description 12
- MIGAKMWKMLYGJX-UHFFFAOYSA-N 3-(5,6-dichloro-2-oxo-1,3-benzoxazol-3-yl)propanoic acid Chemical group ClC=1C(=CC2=C(N(C(O2)=O)CCC(=O)O)C1)Cl MIGAKMWKMLYGJX-UHFFFAOYSA-N 0.000 claims description 11
- PCDYNCVGNLQHQL-LLVKDONJSA-N ClC=1C(=CC2=C(C(=NO2)CCC(=O)O)C=1)O[C@H](C)C1=CC=CC=C1 Chemical compound ClC=1C(=CC2=C(C(=NO2)CCC(=O)O)C=1)O[C@H](C)C1=CC=CC=C1 PCDYNCVGNLQHQL-LLVKDONJSA-N 0.000 claims description 11
- MXKLDYKORJEOPR-UHFFFAOYSA-N 3-(5-fluoro-1h-indol-3-yl)pyrrolidine-2,5-dione Chemical compound C12=CC(F)=CC=C2NC=C1C1CC(=O)NC1=O MXKLDYKORJEOPR-UHFFFAOYSA-N 0.000 claims description 10
- 229940125760 NLG802 Drugs 0.000 claims description 10
- WXTSKOFJNRRBHP-DLBZAZTESA-N N[C@@H](CC(C)C)C(=O)N[C@H](CC1=CN(C2=CC=CC=C12)C)C(=O)OCC Chemical compound N[C@@H](CC(C)C)C(=O)N[C@H](CC1=CN(C2=CC=CC=C12)C)C(=O)OCC WXTSKOFJNRRBHP-DLBZAZTESA-N 0.000 claims description 10
- 210000000115 thoracic cavity Anatomy 0.000 claims description 10
- APPLEPDDBNLZPX-UHFFFAOYSA-N 2-amino-4-hydroxy-4-(3-hydroxyphenyl)butanoic acid Chemical group OC(=O)C(N)CC(O)C1=CC=CC(O)=C1 APPLEPDDBNLZPX-UHFFFAOYSA-N 0.000 claims description 9
- KBJZPNMDKSNLIZ-UHFFFAOYSA-N 2-azaniumyl-4-(3-nitrophenyl)-4-oxobutanoate Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC([N+]([O-])=O)=C1 KBJZPNMDKSNLIZ-UHFFFAOYSA-N 0.000 claims description 9
- 208000008287 Arterial tortuosity syndrome Diseases 0.000 claims description 9
- 208000017570 Shprintzen-Goldberg syndrome Diseases 0.000 claims description 9
- 201000010251 cutis laxa Diseases 0.000 claims description 9
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 8
- 208000027896 Aortic valve disease Diseases 0.000 claims description 8
- 101000799194 Homo sapiens Serine/threonine-protein kinase receptor R3 Proteins 0.000 claims description 8
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 8
- 201000001508 Loeys-Dietz syndrome 3 Diseases 0.000 claims description 8
- 208000026928 Turner syndrome Diseases 0.000 claims description 8
- 201000002429 X-linked Alport syndrome Diseases 0.000 claims description 8
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 208000003215 hereditary nephritis Diseases 0.000 claims description 8
- 102000005862 Angiotensin II Human genes 0.000 claims description 7
- 229950006323 angiotensin ii Drugs 0.000 claims description 7
- 108020003175 receptors Proteins 0.000 claims description 7
- WIKGAEMMNQTUGL-UHFFFAOYSA-N 5-[(7-chloro-1h-indol-3-yl)methyl]-3-methylimidazolidine-2,4-dione Chemical compound O=C1N(C)C(=O)NC1CC1=CNC2=C(Cl)C=CC=C12 WIKGAEMMNQTUGL-UHFFFAOYSA-N 0.000 claims description 6
- 101000595913 Homo sapiens Procollagen glycosyltransferase Proteins 0.000 claims description 6
- 101710143112 Mothers against decapentaplegic homolog 4 Proteins 0.000 claims description 6
- 230000002490 cerebral effect Effects 0.000 claims description 6
- 208000018695 congenital heart malformation Diseases 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 102100031788 E3 ubiquitin-protein ligase MYLIP Human genes 0.000 claims 8
- 101710190174 E3 ubiquitin-protein ligase MYLIP Proteins 0.000 claims 8
- FAEYXAMDOMXIJF-ZETCQYMHSA-N (2s)-2-[(2-methoxybenzoyl)amino]propanoic acid Chemical compound COC1=CC=CC=C1C(=O)N[C@@H](C)C(O)=O FAEYXAMDOMXIJF-ZETCQYMHSA-N 0.000 claims 7
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 claims 4
- 102100035199 Procollagen glycosyltransferase Human genes 0.000 claims 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 claims 1
- 239000002207 metabolite Substances 0.000 abstract description 46
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract description 26
- 230000004060 metabolic process Effects 0.000 abstract description 11
- 210000004509 vascular smooth muscle cell Anatomy 0.000 abstract description 5
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 abstract description 4
- 239000003797 essential amino acid Substances 0.000 abstract description 4
- 235000020776 essential amino acid Nutrition 0.000 abstract description 4
- 230000000770 proinflammatory effect Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 193
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 description 184
- 102000057288 Tryptophan 2,3-dioxygenases Human genes 0.000 description 184
- 230000009977 dual effect Effects 0.000 description 96
- 108020004459 Small interfering RNA Proteins 0.000 description 80
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 76
- 239000011780 sodium chloride Substances 0.000 description 76
- 239000003981 vehicle Substances 0.000 description 65
- 210000000709 aorta Anatomy 0.000 description 48
- 238000001543 one-way ANOVA Methods 0.000 description 37
- 238000013105 post hoc analysis Methods 0.000 description 37
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 36
- 238000011201 multiple comparisons test Methods 0.000 description 35
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 31
- 102000004190 Enzymes Human genes 0.000 description 31
- 108090000790 Enzymes Proteins 0.000 description 31
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 28
- 238000003119 immunoblot Methods 0.000 description 27
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 description 26
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 25
- 238000001802 infusion Methods 0.000 description 24
- 239000000126 substance Substances 0.000 description 24
- 102100037850 Interferon gamma Human genes 0.000 description 22
- 108010074328 Interferon-gamma Proteins 0.000 description 22
- 210000005119 human aortic smooth muscle cell Anatomy 0.000 description 22
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 22
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 21
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 21
- 102000013918 Apolipoproteins E Human genes 0.000 description 19
- 108010025628 Apolipoproteins E Proteins 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 19
- -1 compound 5-methylpyrazine-2- carboxylic acid-4-oxide Chemical class 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 15
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 14
- 102000004020 Oxygenases Human genes 0.000 description 14
- 108090000417 Oxygenases Proteins 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 229910052805 deuterium Inorganic materials 0.000 description 13
- 239000001963 growth medium Substances 0.000 description 13
- 238000011532 immunohistochemical staining Methods 0.000 description 13
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 13
- FBZONXHGGPHHIY-UHFFFAOYSA-N xanthurenic acid Chemical compound C1=CC=C(O)C2=NC(C(=O)O)=CC(O)=C21 FBZONXHGGPHHIY-UHFFFAOYSA-N 0.000 description 13
- 102000008186 Collagen Human genes 0.000 description 12
- 108010035532 Collagen Proteins 0.000 description 12
- 102000016942 Elastin Human genes 0.000 description 12
- 108010014258 Elastin Proteins 0.000 description 12
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 12
- 102100026803 Type-1 angiotensin II receptor Human genes 0.000 description 12
- 229920001436 collagen Polymers 0.000 description 12
- 229920002549 elastin Polymers 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 11
- 238000000546 chi-square test Methods 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 238000012544 monitoring process Methods 0.000 description 11
- 229940081066 picolinic acid Drugs 0.000 description 11
- 238000002604 ultrasonography Methods 0.000 description 11
- 208000026350 Inborn Genetic disease Diseases 0.000 description 10
- 210000000702 aorta abdominal Anatomy 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 208000016361 genetic disease Diseases 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 230000036470 plasma concentration Effects 0.000 description 10
- 230000000087 stabilizing effect Effects 0.000 description 10
- 210000004204 blood vessel Anatomy 0.000 description 9
- 210000002808 connective tissue Anatomy 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 238000007805 zymography Methods 0.000 description 9
- 201000001320 Atherosclerosis Diseases 0.000 description 8
- 206010004552 Bicuspid aortic valve Diseases 0.000 description 8
- 208000021654 bicuspid aortic valve disease Diseases 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 238000011002 quantification Methods 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 108010085238 Actins Proteins 0.000 description 7
- 101000875067 Homo sapiens Collagen alpha-2(I) chain Proteins 0.000 description 7
- 108010068073 Kynurenine-oxoglutarate transaminase Proteins 0.000 description 7
- 208000034259 Vascular Ehlers-Danlos syndrome Diseases 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 210000002798 bone marrow cell Anatomy 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000002591 computed tomography Methods 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 229960003966 nicotinamide Drugs 0.000 description 7
- 235000005152 nicotinamide Nutrition 0.000 description 7
- 239000011570 nicotinamide Substances 0.000 description 7
- 229960003512 nicotinic acid Drugs 0.000 description 7
- 235000001968 nicotinic acid Nutrition 0.000 description 7
- 239000011664 nicotinic acid Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 6
- 241000208125 Nicotiana Species 0.000 description 6
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 6
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 6
- 210000000038 chest Anatomy 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 108060002895 fibrillin Proteins 0.000 description 6
- 102000013370 fibrillin Human genes 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229950009034 indoximod Drugs 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- 210000004115 mitral valve Anatomy 0.000 description 6
- 208000001491 myopia Diseases 0.000 description 6
- 230000004379 myopia Effects 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 102100036213 Collagen alpha-2(I) chain Human genes 0.000 description 5
- 206010061818 Disease progression Diseases 0.000 description 5
- 101000614988 Homo sapiens Mediator of RNA polymerase II transcription subunit 12 Proteins 0.000 description 5
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 210000002376 aorta thoracic Anatomy 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 208000009854 congenital contractural arachnodactyly Diseases 0.000 description 5
- 238000010217 densitometric analysis Methods 0.000 description 5
- 230000005750 disease progression Effects 0.000 description 5
- 238000002595 magnetic resonance imaging Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical compound Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 description 4
- JRYYVMDEUJQWRO-UHFFFAOYSA-N 2-methylnicotinamide Chemical compound CC1=NC=CC=C1C(N)=O JRYYVMDEUJQWRO-UHFFFAOYSA-N 0.000 description 4
- 206010060874 Aortic rupture Diseases 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 102100033775 Collagen alpha-5(IV) chain Human genes 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 102100040062 Indoleamine 2,3-dioxygenase 2 Human genes 0.000 description 4
- 101710120841 Indoleamine 2,3-dioxygenase 2 Proteins 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 4
- 102100021070 Mediator of RNA polymerase II transcription subunit 12 Human genes 0.000 description 4
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 4
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 4
- 102100030830 Nicotinate-nucleotide pyrophosphorylase [carboxylating] Human genes 0.000 description 4
- 102100034136 Serine/threonine-protein kinase receptor R3 Human genes 0.000 description 4
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 229960004853 betadex Drugs 0.000 description 4
- 208000021138 brain aneurysm Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000004087 circulation Effects 0.000 description 4
- KACPVQQHDVBVFC-OIFXTYEKSA-N cis,cis-2-amino-3-(3-oxoprop-1-enyl)but-2-enedioic acid Chemical compound OC(=O)C(/N)=C(/C(O)=O)\C=C/C=O KACPVQQHDVBVFC-OIFXTYEKSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 108090000277 nicotinate-nucleotide diphosphorylase (carboxylating) Proteins 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 238000003127 radioimmunoassay Methods 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 3
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 3
- 108010085793 Neurofibromin 1 Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 210000002551 anterior cerebral artery Anatomy 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 210000001841 basilar artery Anatomy 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000004004 carotid artery internal Anatomy 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 230000003205 diastolic effect Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 3
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 238000007726 management method Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 210000003657 middle cerebral artery Anatomy 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 210000003388 posterior cerebral artery Anatomy 0.000 description 3
- 238000007634 remodeling Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 230000003313 weakening effect Effects 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- JVICQEYUDFKRNP-UHFFFAOYSA-N 1h-indol-2-amine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=C2NC(N)=CC2=C1 JVICQEYUDFKRNP-UHFFFAOYSA-N 0.000 description 2
- QCGTZPZKJPTAEP-REDYYMJGSA-N 2-aminomuconic 6-semialdehyde Chemical compound OC(=O)C(/N)=C\C=C/C=O QCGTZPZKJPTAEP-REDYYMJGSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102100036732 Actin, aortic smooth muscle Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
- 101100328883 Arabidopsis thaliana COL1 gene Proteins 0.000 description 2
- 101100328890 Arabidopsis thaliana COL3 gene Proteins 0.000 description 2
- 108010018854 Arylformamidase Proteins 0.000 description 2
- 208000010061 Autosomal Dominant Polycystic Kidney Diseases 0.000 description 2
- 108010074051 C-Reactive Protein Proteins 0.000 description 2
- 102100032752 C-reactive protein Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000004031 Carboxy-Lyases Human genes 0.000 description 2
- 108090000489 Carboxy-Lyases Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- 108010037645 Cytokine TWEAK Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102100028067 EGF-containing fibulin-like extracellular matrix protein 2 Human genes 0.000 description 2
- 102100033167 Elastin Human genes 0.000 description 2
- 102100037241 Endoglin Human genes 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 102100031509 Fibrillin-1 Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- 101000929319 Homo sapiens Actin, aortic smooth muscle Proteins 0.000 description 2
- 101000710886 Homo sapiens Collagen alpha-5(IV) chain Proteins 0.000 description 2
- 101001060248 Homo sapiens EGF-containing fibulin-like extracellular matrix protein 2 Proteins 0.000 description 2
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 2
- 101000846893 Homo sapiens Fibrillin-1 Proteins 0.000 description 2
- 101001022780 Homo sapiens Myosin light chain kinase, smooth muscle Proteins 0.000 description 2
- 101001000104 Homo sapiens Myosin-11 Proteins 0.000 description 2
- 101001069727 Homo sapiens Paired mesoderm homeobox protein 1 Proteins 0.000 description 2
- 101000595904 Homo sapiens Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 Proteins 0.000 description 2
- 101000635958 Homo sapiens Transforming growth factor beta-2 proprotein Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 102000013519 Lipocalin-2 Human genes 0.000 description 2
- 108010051335 Lipocalin-2 Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 2
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 2
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102100035044 Myosin light chain kinase, smooth muscle Human genes 0.000 description 2
- 102100036639 Myosin-11 Human genes 0.000 description 2
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 2
- 102000004722 NADPH Oxidases Human genes 0.000 description 2
- 108010002998 NADPH Oxidases Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 2
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 description 2
- 102100023181 Neurogenic locus notch homolog protein 1 Human genes 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 108010029755 Notch1 Receptor Proteins 0.000 description 2
- 102000004264 Osteopontin Human genes 0.000 description 2
- 108010081689 Osteopontin Proteins 0.000 description 2
- 102000008108 Osteoprotegerin Human genes 0.000 description 2
- 108010035042 Osteoprotegerin Proteins 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102100033786 Paired mesoderm homeobox protein 1 Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100035202 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 Human genes 0.000 description 2
- 102100035703 Prostatic acid phosphatase Human genes 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- 241000720974 Protium Species 0.000 description 2
- 208000004717 Ruptured Aneurysm Diseases 0.000 description 2
- 108091006307 SLC2A10 Proteins 0.000 description 2
- 102100039670 Solute carrier family 2, facilitated glucose transporter member 10 Human genes 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- 108010008125 Tenascin Proteins 0.000 description 2
- 102000007000 Tenascin Human genes 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 108010011702 Transforming Growth Factor-beta Type I Receptor Proteins 0.000 description 2
- 102000004060 Transforming Growth Factor-beta Type II Receptor Human genes 0.000 description 2
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 description 2
- 102100030737 Transforming growth factor beta-2 proprotein Human genes 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 102100024584 Tumor necrosis factor ligand superfamily member 12 Human genes 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 208000022185 autosomal dominant polycystic kidney disease Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 238000010968 computed tomography angiography Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000001066 destructive effect Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 208000015502 familial bicuspid aortic valve Diseases 0.000 description 2
- 208000016470 familial thoracic aortic aneurysm and aortic dissection Diseases 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000005934 immune activation Effects 0.000 description 2
- 230000000984 immunochemical effect Effects 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000005445 isotope effect Effects 0.000 description 2
- 210000003127 knee Anatomy 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 238000011458 pharmacological treatment Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 208000024126 vascular type Ehlers-Danlos syndrome Diseases 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- APAZHLOKLBSFEQ-QMMMGPOBSA-N (2s)-2-[benzoyl(methoxy)amino]propanoic acid Chemical compound OC(=O)[C@H](C)N(OC)C(=O)C1=CC=CC=C1 APAZHLOKLBSFEQ-QMMMGPOBSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- CCRYOAJLCYVEKC-UHFFFAOYSA-N 6-amino-6-hydroxycyclohexa-2,4-diene-1-carboxylic acid Chemical compound NC1(O)C=CC=CC1C(O)=O CCRYOAJLCYVEKC-UHFFFAOYSA-N 0.000 description 1
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 1
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 206010063847 Arachnodactyly Diseases 0.000 description 1
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 1
- 108090000121 Aromatic-L-amino-acid decarboxylases Proteins 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 101001015517 Betula pendula Germin-like protein 1 Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100035654 Cathepsin S Human genes 0.000 description 1
- 108090000613 Cathepsin S Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 108010072220 Cyclophilin A Proteins 0.000 description 1
- 102000012192 Cystatin C Human genes 0.000 description 1
- 108010061642 Cystatin C Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000003154 D dimer Substances 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 description 1
- 208000003164 Diplopia Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010013952 Dysphonia Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102100032057 ETS domain-containing protein Elk-1 Human genes 0.000 description 1
- 101710130337 ETS domain-containing protein Elk-1 Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100024520 Ficolin-3 Human genes 0.000 description 1
- 101710155250 Ficolin-3 Proteins 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000010473 Hoarseness Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001021858 Homo sapiens Kynureninase Proteins 0.000 description 1
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 1
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229940122439 Hydroxylase inhibitor Drugs 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229940043367 IDO1 inhibitor Drugs 0.000 description 1
- 208000000523 Infected Aneurysm Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 208000014651 Meester-Loeys syndrome Diseases 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- 208000033115 Mycotic aneurysm Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108010050808 Procollagen Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039330 Ruptured cerebral aneurysm Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 208000035459 X-linked severe syndromic thoracic aortic aneurysm and dissection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 208000037919 acquired disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical class O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 description 1
- 208000029444 double vision Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 238000002297 emergency surgery Methods 0.000 description 1
- 239000000066 endothelium dependent relaxing factor Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 108010092470 extradiol dioxygenase Proteins 0.000 description 1
- 108010052295 fibrin fragment D Proteins 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 102000028416 insulin-like growth factor binding Human genes 0.000 description 1
- 108091022911 insulin-like growth factor binding Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000031261 interleukin-10 production Effects 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- AWNIIYIQMZGLMO-UHFFFAOYSA-N n-(4-phenyl-1,3-thiazol-2-yl)benzenesulfonamide Chemical class C=1C=CC=CC=1S(=O)(=O)NC(SC=1)=NC=1C1=CC=CC=C1 AWNIIYIQMZGLMO-UHFFFAOYSA-N 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 150000002814 niacins Chemical group 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 238000012148 non-surgical treatment Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000009543 pathological alteration Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NVZLBPXTJTXPDC-UHFFFAOYSA-N pyrrolo[3,4-e]benzimidazole Chemical class C1=CC2=NC=NC2=C2C=NC=C21 NVZLBPXTJTXPDC-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 208000018316 severe headache Diseases 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 230000026799 smooth muscle cell apoptotic process Effects 0.000 description 1
- 208000026843 stiff neck Diseases 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 230000037197 vascular physiology Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000020812 vitamin status Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- This invention provides methods for identifying and treating a subject having an aneurysm, including an abdominal aortic aneurysm, cerebral aneurysm, or thoracic aortic aneurysm, or is at risk of developing an aneurysm due to, for example, an underlying genetic disorder, for example Marfan syndrome and like disorders, which makes the subject prone to the development of an aneurysm.
- an aneurysm including an abdominal aortic aneurysm, cerebral aneurysm, or thoracic aortic aneurysm
- Aneurysms are excessive localized enlargements of an artery caused by a weakening of the artery wall.
- the balloon-like bulges have increasing risk of rupture as they increase in size, in addition to be being a potential site for thrombosis and the eventual formation of an embolism.
- Aneurysms may be the result of a hereditary condition or a later acquired disease.
- Three particularly lethal types of aneurysms upon rupture are abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA), and cerebral aneurysm (CA).
- AAA abdominal aortic aneurysms
- AAA Abdominal aortic aneurysm
- AAA intraluminal thrombus
- AAA's are asymptomatic, screening programs have been established to target at- risk groups, commonly men aged >60 years. Most, if not all, of these programs utilize ultrasound to identify AAA. Ultrasound is also commonly used to monitor disease progression, since the natural course of most AAAs is to gradually expand, thereby increasing the risk of rupture. Specifically, maximal AAA diameter as measured by ultrasound is the most commonly used surrogate marker of rupture risk.
- MFS Marfan syndrome
- a thoracic aortic aneurysm is an aortic aneurysm that presents primarily in the thorax. TAAs, which have an estimated annual incidence of 10.4 per 100,000 people, are typically clinically silent yet potentially fatal, as their natural history is to progressively expand until dissection or rupture occurs. Brownstein AJ, Ziganshin BA, Kuivaniemi H, Body SC, Bale AE, Elefteriades JA. Genes Associated with Thoracic Aortic Aneurysm and Dissection: An Update and Clinical Implications. AORTA (Stamford). 2017;5(1): 11-20.
- TAAs Other disorders associated with TAAs include Syndromes associated with thoracic aortic aneurysms include Marfan syndrome (MFS), Loeys- Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), familial thoracic aortic aneurysms and dissections (TAAD), autosomal dominant polycystic kidney disease (ADPKD), bicuspid aortic valve (BAV), Meester-Loeys syndrome, cutis laxa, contractural arachnodactyly, periventricular nodular heterotpia, Shprintzen-Goldberg syndrome, arterial tortuosity syndrome, and neurofibromatosis type 1 (NF1).
- MFS Marfan syndrome
- LDS Loeys- Dietz syndrome
- EDS Ehlers-Danlos syndrome
- TAAD familial thoracic aortic aneurysms and dissections
- ADPKD autosomal dominant polyc
- Atherosclerosis is the principal cause of descending aortic aneurysms, while aneurysms of the aortic arch may be due to dissection, atherosclerosis or inflammation.
- the size cut off for aortic aneurysm is crucial to its treatment.
- a thoracic aorta greater than 4.5 cm is generally defined as aneurysmal, while a size greater than 6 cm is the distinction for treatment, which can be either endovascular or surgical, with the former reserved for pathology at the descending aorta. Indication for surgery may depend upon the size of the aneurysm. Aneurysms in the ascending aorta may require surgery at a smaller size than aneurysms in the descending aorta.
- Cerebral aneurysms affect about 5 percent of the population and occur when the wall of a blood vessel in the brain becomes weakened and bulges or balloons out.
- Pre-rupture treatments are generally limited to surgical clipping or endovascular coiling or a flow diverter can be used to seal off an unruptured brain aneurysm and help prevent a future rupture.
- the known risks of the procedures may outweigh the potential benefit.
- Cerebral aneurysms are usually found at the base of the brain just inside the skull, in an area called the subarachnoid space. Rupture of these cerebral aneurysms results in bleeding into the space around the brain and is often referred to as subarachnoid hemorrhage (SAH). This kind of hemorrhage can lead to a stroke, coma and/or death.
- SAH subarachnoid hemorrhage
- the present invention provides methods for detecting and/or treating a subject having an aneurysm or at risk for developing an aneurysm. It has been discovered that a key metabolite of the kynurenine (Kyn) pathway, a major route for the metabolism of essential amino acid tryptophan (Trp) into nicotinamide adenine dinucleotide (NAD+), plays a critical role in the formation of aneurysms, for example abdominal aortic aneurysms. In particular, it has been discovered that 3-Hydroxyanthranilic acid (3-HAA), a product of kynureninase (KYNU) (see Fig.
- 3-Hydroxyanthranilic acid 3-Hydroxyanthranilic acid
- the identification of 3-HAA as a causative agent in the formation of aneurysms provides an attractive target in the treatment of aneurysms. Accordingly, the present invention provides methods for treating formed aneurysms by administering compounds that inhibit the formation of 3-HAA or alter the effects of excessive 3-HAA formation.
- the administration of certain KYN pathway metabolism inhibitors effectively inhibits the formation of 3-HAA and reduces aneurysm formation. Importantly, such inhibitors are also effective at reducing or delaying the progression of aneurysms once formed (see, for example, Example 15).
- inhibitors of KYNU are especially effective at inhibiting the formation of 3-HAA, as well as inhibiting the formation of and progression of aneurysms, compared to KYN pathway inhibitors that act further upstream in the KYN pathway (see, for example, Example 15 and Figures 30, 31 A, 3 IB, 31C, and 32C).
- the administration of the compound 5-methylpyrazine-2- carboxylic acid-4-oxide (acipimox) which mitigates the effects of excessive levels of 3-HAA (see, for example, Example 17), significantly reduces aneurysm formation and reduces or delays aneurysm progression (see Examples 12 and 13).
- the discovery of effective treatments for reducing or delaying aneurysm progression provides a novel pharmaceutical approach to treating formed aneurysms, thus eliminating, diminishing, and/or delaying the requirement for more invasive surgical interventions.
- the combination of earlier detection via 3-HAA level determinations as well as more patient-friendly treatment methods may provide for improved outcomes in those at risk for developing or who have developed an aneurysm.
- 3-HAA levels in a subject are indicative of the presence of an aneurysm, wherein subjects with an aneurysm have significantly elevated levels of 3-HAA compared to subjects without an aneurysm, and patients who have had a dissected aneurysm have further elevated plasma levels of 3-HAA compared to subjects with non-dissected aneurysms.
- a sample from a subject for example a blood, serum, or plasma sample
- aneurysmal growth i.e., aneurysmal growth; see Example 14
- aneurysmal growth can be monitored and assessed, and if necessary, appropriate intervention undertaken, for example the administration of a suitable pharmaceutical or surgical intervention.
- a method of screening for the presence of an aneurysm in a subject comprising:
- determining the level of 3-HAA present in a sample from the subject i. determining the level of 3-HAA present in a sample from the subject; and ii. comparing the subject's level of 3-HAA to a range of standardized 3-HAA levels derived from individuals without an aneurysm ("normal range");
- an aneurysm is suspected if the subject's 3-HAA level is greater than the normal range.
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 1.5 times (1.5X) the mean of the normal range.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 1.75X the mean of the normal range.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 2. OX the mean of the normal range.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.25X the mean of the normal range. In embodiments, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.5X the mean of the normal range. In embodiments, the method further includes performing a medical imaging technique on the subject if the subject's 3-HAA plasma level is greater than the normal range in order to verify or exclude the presence of an aneurysm.
- the subject if the subject's 3-HAA level is determined to be greater than the normal range, the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth or capable of stabilizing the aneurysm, for example a compound described herein.
- a medical intervention for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth or capable of stabilizing the aneurysm, for example a compound described herein.
- the subject undergoes surgical intervention to repair the aneurysm.
- a method of screening for the presence of an aneurysm in a subject comprising:
- aneurysmal range a range of standardized 3-HAA levels derived from individuals with an aneurysm
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified AAA ("AAA range”).
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified TAA ("TAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified CA ("CA range").
- the method further includes performing a medical imaging technique on a subject with a 3-HAA plasma level within the aneurysmal range in order to verify the presence of an aneurysm.
- the subject's 3-HAA level is determined to be within the aneurysmal range, the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm.
- a method of determining whether an aneurysm in a subject is at risk for dissection comprising:
- determining the level of 3-HAA present in a sample from the subject i. determining the level of 3-HAA present in a sample from the subject; and ii. comparing the subject's level of 3-HAA to a range of standardized 3-HAA levels derived from individuals having a dissected aneurysm ("dissected aneurysmal range");
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected AAA ("dissected AAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected TAA ("dissected TAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected CA ("dissected CA range").
- the method further includes performing a medical imaging technique on a subject with a 3-HAA plasma level within the dissected aneurysmal range in order to verify the presence of an aneurysm.
- the subject's 3-HAA level is determined to be within the dissected aneurysmal range
- the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm, for example an open surgical or endovascular aneurysm repair is performed to repair the AAA, TAA, or CA.
- a method of detecting arterial diameter expansion in an aneurysm in a subject comprising:
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the arterial diameter expansion of an AAA or TAA is an expansion of the diameter of the aorta at the site of the aneurysm ("aortic diameter expansion").
- the arterial diameter expansion of a CA is an expansion of the diameter of the anterior communicating artery, posterior communicating artery, anterior cerebral artery, middle cerebral artery, posterior cerebral artery, internal carotid artery, or the tip of the basilar artery at the site of the aneurysm.
- the method further includes performing a medical imaging technique on a subject with a second level of 3-HAA greater than the first level of 3-HAA in order to verify the presence of arterial diameter expansion in the aneurysm.
- a medical imaging technique on a subject with a second level of 3-HAA greater than the first level of 3-HAA in order to verify the presence of arterial diameter expansion in the aneurysm.
- an open surgical or endovascular aneurysm repair is performed to repair the aneurysm.
- the subject if the subject's second level of 3-HAA is greater than the first level of 3-HAA, the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- a medical intervention for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm, for example an open surgical or endovascular aneurysm repair is performed to repair the AAA, TAA, or CA.
- a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection may further undergo a medical intervention to treat the aneurysm, for example the administration of a suitable compound or composition or a surgical intervention.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering to the subject a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject is treated for the aneurysm by undergoing a surgical intervention, for example open surgical or endovascular aneurysm repair.
- the subject is administered an effective amount of a KYNU inhibitor as a monotherapy, or in combination with another agent.
- the subject is administered an effective amount of a KMO inhibitor as a monotherapy, or alternatively in combination with another agent.
- the subject is administered an effective amount of a KYN pathway inhibitor selected from an indoleamine 2,3 -di oxygenase 1 (IDOl) inhibitor, a tryptophan 2,3-dioxygenase (TD02) inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- IDOl indoleamine 2,3 -di oxygenase 1
- TD02 tryptophan 2,3-dioxygenase
- the subject is administered an effective amount of acipimox.
- acipimox is administered as a monotherapy.
- acipimox is administered in combination with another agent.
- acipimox is administered in combination with a KMO inhibitor.
- acipimox is administered in combination with a KYNU inhibitor.
- the subject is administered an effective amount of a 3-HAO up-regulator.
- the subject with a determined elevated 3-HAA level as described herein is administered a compound selected from fenofibrate, telmisartan, 5-((7-Cl-lH-indol-3-yl)methyl)-3-methylimidazolidine- 2,4-dione) (7-Cl-O-Nec-l), a ⁇ -blocker, angiotensin converting enzyme inhibitor (ACEI), angiotensin II type I receptor (AGTR1) blocker (ARBs), statin, tetracycline/macrolide, ERK inhibitor, losartan, pravastatin, ⁇ -blocker atenolol, the ACEI perindopril, the calcium channel blocker (CCB) verapamil, roxithromycin, ethinyl estradiol, nebivolol, and doxycycline.
- a method of treating a subject having a formed aneurysm comprising administering to the subject an effective amount of a compound described herein.
- the subject is administered an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is administered as a monotherapy.
- the KYNU inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of a KMO inhibitor.
- the KMO inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of acipimox.
- acipimox is administered as a monotherapy.
- acipimox is administered in combination with an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, a KYNU inhibitor, or a combination thereof.
- the subject is administered an effective amount of a 3-HAO up-regulator.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the subject is at risk for developing a dissected aneurysm, for example a dissected AAA, dissected TAA, or dissected CA.
- the subject has an AAA or TAA with an aortic diameter of less than or equal to about 3 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of less than or equal to about 5 cm.
- the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 5 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 7 cm. In some embodiments, the subject has a CA with an arterial diameter of less than or equal to about 5 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 5 mm. In some embodiments, the subj ect has a CA with an arterial diameter of greater than or equal to about 10 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 25 mm.
- the subject is administered an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is administered as a monotherapy.
- the subject is administered an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is administered as a monotherapy.
- the KYNU inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of a KMO inhibitor.
- the KMO inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of acipimox.
- acipimox is administered as a monotherapy.
- acipimox is administered in combination with an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, a KYNU inhibitor, or a combination thereof.
- the subject is administered an effective amount of a 3-HAO up-regulator.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the subject has a genetic disorder associated with an increased risk of aneurysm development.
- the subject has a genetic disorder selected from Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, Familial Thoracic Aortic Aneurysm and Dissection, Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome, Beals syndrome, aneurysms-osteoarthritis syndrome, Shprintzen- Goldberg syndrome, cutis laxa syndrome, aortic valve disease, arterial tortuosity syndrome, X- linked Alport syndrome, Turner syndrome, and Bicuspid Aortic Valve syndrome.
- the subject has a mutation in a gene selected from COL1A1, COL1A2, MED12, PLOD 3, ENG, ACVRL1 or F1, or a combination thereof.
- the subject is administered an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is administered as a monotherapy.
- the KYNU inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of a KMO inhibitor.
- the KMO inhibitor is administered in combination with another compound, for example an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, acipimox, another agent, or a combination thereof.
- the subject is administered an effective amount of acipimox.
- acipimox is administered as a monotherapy.
- acipimox is administered in combination with an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, a KMO inhibitor, a KYMJ inhibitor, or a combination thereof.
- the subject is administered an effective amount of a 3-HAO up-regulator.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- the subject is predisposed to the development of an AAA or TAA.
- the subject is predisposed to the development of a CA.
- the subject has a genetic disorder associated with an increased risk of AAA or TAA development.
- the subject has a genetic disorder selected from Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, Familial Thoracic Aortic Aneurysm and Dissection, Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome, Beals syndrome, aneurysms-osteoarthritis syndrome, Shprintzen- Goldberg syndrome, cutis laxa syndrome, aortic valve disease, arterial tortuosity syndrome, X- linked Alport syndrome, Turner syndrome, and Bicuspid Aortic Valve syndrome.
- the subject has a mutation in a gene selected from COL1A1, COL1A2, MED12, PLOD 3, ENG, ACVRL1 or F1, or a combination thereof.
- the KYNU inhibitor may be selected from 2-Amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid, (4R)-dihydro-L-kynurenine (4S)-dihydro-L-kynurenine,
- Methoxybenzoylalanine OMBA
- NBA m-Nitrobenzoyl
- the KMO inhibitor may be selected from GSK180, (R)-3-(5-chloro-6-(l-phenylethoxy)benzo[d]isoxazol-3- yl)propanoic acid, CHDI-340246, des-amino FCE 28833, UPF 648, and Ro-61-8048.
- the IDOl inhibitor may be selected from 1-methyl-D-tryptophan, navoximod, NLG802, epacadostat, BMS-
- kits for analyzing the level of 3- HAA in a subject includes at least one antibody directed to 3-HAA.
- the kit further includes a control protein or molecule in an amount useful in normalizing or standardizing levels of 3-HAA.
- FIG. 1A depicts representative photographs showing the macroscopic features of Angll- induced aneurysms in ApoE _/" and ApoE ⁇ VIDO " " mice administered with saline or Angll (100 ng/min per kg) for 4 weeks.
- the arrow indicates typical abdominal aortic aneurysm (AAA).
- FIG. IB is a bar graph that shows the incidence of Angll-induced AAA in ApoE " ' " and ApoE ⁇ /IDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline, and the y-axis shows AAA incidence in percent. * P ⁇ 0.01 vs.
- mice # P ⁇ 0.01 vs. Angll-infused ApoE _/" mice.
- N 8 in each group of ApoE " ' ⁇ and ApcE ⁇ /IDO " " mice infused with saline.
- N 15 for Angll-infused ApoE mice.
- N 12 for Angll-infused ApoE ⁇ VIDO " " mice.
- FIG. 1C is a bar graph that shows the maximum abdominal aortic diameter in ApoE _/" and ApoE ⁇ /IDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows maximal abdominal aortic diameter in millimeters.
- P values were obtained by a ⁇ 2 test in band by a one-way analysis of variance (ANOVA) with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars represent the standard error of the mean.
- ANOVA analysis of variance
- FIG. ID is a bar graph that shows the total aortic weight in ApoE _/" and ApoE ⁇ VIDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows the total aortic weight per body weight in percent.
- P values were obtained by a ⁇ 2 test in band by a one-way analysis of variance (ANOVA) with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars represent the standard error of the mean.
- ANOVA analysis of variance
- FIG. IE shows representative staining with hematoxylin and eosin (H&E), a-actin, Van Gieson's (elastin), and Masson's Trichrome (collagen) in the suprarenal aortas of ApoE _/" and ApoE ⁇ /IDO- - mice after administration of saline or Angll (1000 ng/min per kg) for 4 weeks.
- FIG. IF is a bar graph that shows the grade of elastin degradation in ApoE _/" and ApoE _/" /IDO _/" mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows the grade of elastin degradation.
- P values were obtained by a ⁇ 2 test in band by a one-way analysis of variance (ANOVA) with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars represent the standard error of the mean.
- ANOVA analysis of variance
- FIG. 1G is a bar graph that shows the amount of collagen deposition in ApoE _/" and ApoE " ⁇ IDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows the collagen area in percent.
- P values were obtained by a ⁇ 2 test in band by a one-way analysis of variance (ANOVA) with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars represent the standard error of the mean.
- ANOVA analysis of variance
- Angll-infused ApoE _/ mice.
- N 8 in each group of ApoE _/" and ApoE ⁇ VIDO " " mice infused with saline.
- n 15 for Angll-infused ApoE _/” mice.
- n 12 for Angll-infused ApoE ⁇ VIDO ⁇ mice.
- FIG. 2A shows representative immunohistochemical staining for interferon (IFN)-y, IDO, and MMP2 in the suprarenal aortas of ApoE _/” and ApoE ⁇ VIDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- IFN interferon
- MMP2 MMP2
- FIG. 2B is a bar graph that shows quantification of interferon (IFN)-y, IDO, and MMP2 in the suprarenal aortas of ApoE _/" and ApoE ⁇ VIDO ⁇ mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the mouse genotype, and the y-axis shows the quantification score.
- FIG. 2C is a bar graph that shows the serum concentration of Kyn detected in ApoE _/" and ApoE ⁇ /IDO- - mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows micromolar Kyn concentration.
- FIG. 2D is a bar graph that shows the serum concentration of tryptophan (Trp) detected in ⁇ " and ApoE ⁇ /IDO " - mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the administration of saline or Angll, and the y-axis shows micromolar Trp concentration.
- P values were obtained by a one- way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 2E shows protein expression of IFN- ⁇ , IDO, and MMP2 in the suprarenal aortas of
- ApoE _/ mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- Beta-actin was used as a loading control.
- FIG. 2F is a zymogram that shows MMP2 activity in the suprarenal aortas of ApoE _/" and ApoE ⁇ /IDO- - mice administered saline or Angll (1000 ng/min per kg) for 4 weeks. Beta-actin was used as a loading control.
- FIG. 3 A depicts representative photographs of the macroscopic features of Angll-induced aneurysms in ApoE _/” and ApoE ⁇ VIDO " " mice reconstituted with ApoE _/” or ApoE “/_ /IDO +/+ bone marrow cells, followed by 4 weeks of saline or Angll infusion (1000 ng/min per kg). Arrows indicate typical abdominal aortic aneurysm (AAA).
- FIG. 3B is a bar graph that shows the incidence of Angll-induced AAA in ApoE _/"
- ApoE ⁇ /IDO- - mice reconstituted with ApoE _/" or ApoE "/ 7IDO +/+ bone marrow cells, followed by 4 weeks of saline or Angll infusion (1000 ng/min per kgO.
- the x-axis shows the mouse genotype, and the y-axis shows the AAA incidence in percent.
- N 10-15 per group.
- BM bone marrow; NS, not significant.
- FIG. 3C is a bar graph that shows the maximal abdominal aortic diameter in ApoE _/" and ApoE ⁇ /IDO- - mice reconstituted with ApoE _/” or ApoE "/ 7IDO +/+ bone marrow cells, followed by 4 weeks of saline or Angll infusion (1000 ng/min per kg).
- the x-axis shows the mouse genotype, and the y-axis shows the maximal abdominal aortic diameter in millimeters.
- N 10-15 per group.
- BM bone marrow
- NS not significant.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 3D is a bar graph that shows the total aortic weight in ApoE _/" and ApoE ⁇ VIDO " " mice reconstituted with ApoE _/” or ApoE "/_ /IDO +/+ bone marrow cells, followed by 4 weeks of saline or Angll infusion (1000 ng/min per kg).
- the x-axis shows the mouse genotype, and the y-axis shows the total aortic weight per body weight in percent.
- N 10-15 per group.
- BM bone marrow; NS, not significant.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 4A is an immunoblot, zymogram, and bar graph for cultured HASMCs that were either untreated (control; Con) or treated with IFN- ⁇ combined with the indicated concentrations of exogenous Trp for 48 hours.
- Pro-MMP2, IDO, and glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) proteins were detected by immunoblotting.
- MMP2 activities in the culture medium were detected by zymography.
- Trp and Kyn levels in the culture medium were detected by high- performance liquid chromatography (HPLC). Three independent experiments were performed for all quantitative data. The error bars are standard error of the mean.
- FIG. 4B is an immunoblot, zymogram, and bar graph for cultured HASMCs that were either untreated (control; Con) or treated with IFN- ⁇ and 500 ⁇ Trp for 48 hours.
- Pro-MMP2, IDO, and glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) proteins were detected by immunoblotting.
- MMP2 activities in the culture medium were detected by zymography.
- Trp and Kyn levels in the culture medium were detected by high-performance liquid chromatography (HPLC). Three independent experiments were performed for all quantitative data. The error bars are standard error of the mean.
- FIG. 4C is an immunblot, zymogram, and bar graph for HASMCs that were transfected with control siRNA or IDO siRNA and treated with DMSO (control) or IFN- ⁇ in the presence of absence of 500 ⁇ Trp for 48 hours.
- Pro-MMP2, IDO, and glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) proteins were detected by immunoblotting.
- MMP2 activities in the culture medium were detected by zymography.
- Trp and Kyn levels in the culture medium were detected by high-performance liquid chromatography (HPLC). Three independent experiments were performed for all quantitative data. The error bars are standard error of the mean.
- FIG. 5 A is an immunoblot and zymogram for cultured HASMCs that were either untreated (control; Con) or treated with the indicated metabolites of Trp degradation (Kyn: 100 ⁇ ; 3- hydroxykynurenine [3-HK]: 100 ⁇ ; kynurenic acid [KA]: 75 ⁇ ; anthranilic acid [AA]: 100 ⁇ ; 3-HAA: 200 ⁇ ; xanthurenic acid [XA]: 200 ⁇ ; quinolinic acid [QA]: 1 mM) for 48 hours.
- Pro-MMP2 was detected by immunoblotting.
- Beta-actin was used as a loading control, and MMP2 activities in the culture medium were detected by zymography. Representative data from three independent experiments are shown.
- FIG. 5B is an immunoblot and zymogram for cultured HASMCs that were incubated with the indicated concentrations of 3-HAA for 48 hours.
- Pro-MMP2 and phosphorylated (p)-Elkl were detected by immunoblotting.
- GAPDH was used as a loading control, and MMP2 activities in the culture medium were detected by zymography. Representative data from three independent experiments are shown.
- FIG. 5C is an immunoblot and zymogram for cultured HASMCs that were incubated with 200 ⁇ 3-HAA for the indicated time points.
- Pro-MMP2 and p-Elkl were detected by immunoblotting.
- GAPDH was used as a loading control, and MMP2 activities in the culture medium were detected by zymography. Representative data from three independent experiments are shown.
- FIG. 5D shows cultured HASMCs that were transfected with control siRNA, IDO siRNA, or kynureninase (KYNU) siRNA and treated with vehicle (control) or IFN- ⁇ with the addition of 500 ⁇ Trp for 48 hours.
- a conjugated 3-HAA antibody was used to detected endogenous 3- HAA in HASMCs, and cells were counterstained with a nuclear stain (DAPI).
- FIG. 5E is a bar graph that shows quantitative analysis of the fluorescence intensity of intracellular 3-HAA in cultured HASMCs that were transfected with control siRNA, IDO siRNA, or kyureninase (KYNU) siRNA and treated with vehicle (control) or IFN- ⁇ with the addition of 500 ⁇ Trp for 48 hours.
- a conjugated 3-HAA antibody was used to detected endogenous 3- HAA in HASMCs, and cells were counterstained with a nuclear stain (DAPI).
- the x-axis shows treatment with IFN- ⁇ or Trp, and the y-axis shows integrated intensity as a percent of the control. * P ⁇ 0.01 vs. scrambled siRNA without IFN-y, # P ⁇ 0.01 vs.
- FIG. 5F is an immunoblot and zymogram for cultured HASMCs that were transfected with control siRNA, IDO siRNA, or kynureninase (KYNU) siRNA and treated with vehicle (control) or IFN- ⁇ with the addition of 500 ⁇ Trp for 48 hours.
- Pro-MMP2, IDO, and KNU proteins were detected by immunoblotting.
- GAPDH was used as a loading control, and MMP2 activities in the culture medium were detected b zymography. Representative data from three independent experiments are shown.
- 6A shows representative immunohistochemical staining for 3-HAA in the suprarenal aortas of ApoE _/” and ApoE ⁇ VIDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- FIG. 6B is a bar graph that shows immunohistochemical staining quantification for 3-HAA in the suprarenal aortas of ApoE _/" and ApoE ⁇ VIDO " " mice administered saline or Angll (1000 ng/min per kg) for 4 weeks.
- N 8-10 per group.
- P values were obtained by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 6H is an immunoblot and zymogram for aortas isolated from ApoE _/" and ApoE _/" /IDO " " mice that were treated with vehicle or 400 ⁇ 3-HAA for 38 hours ex vivo.
- MMP2, Pro- MMP2, and GAPDH protein expression in the aortas was detected by immunoblotting, and MMP2 activity in the aortas and supernatants were detected by zymography.
- N 8 per group.
- FIG. 7A depict representative photographs showing the macroscopic features of Angll induced aneurysms in ApoE _/" mice that were transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- N l 0-12 in each group.
- FIG. 7B is a bar graph that shows the incidence of Angll-induced AAA in ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis show the siRNA transfected, and the y-axis shows AAA incidence in percent.
- N 10-12 in each group.
- FIG. 7C is a bar graph that shows the maximal abdominal aortic diameter in ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the siRNA transfected, and the y-axis shows the maximal abdominal aortic diameter in millimeters.
- N l 0-12 in each group.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 7D is a bar graph that shows the total aortic weight in ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the siRNA transfected, and the y-axis shows the total aortic weight per body weight in percent.
- N 10-12 in each group.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 7E shows representative immunoblotting and staining with H&E, a-actin, Van Gieson's, and Masson's Trichrome stain in the suprarenal aortas of ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- N l 0-12 in each group.
- FIG. 7F is a bar graph that shows the grade of elastin degradation in the aortic wall of ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis shows the siRNA transfected, and the y-axis shows the grade of elastin degradation.
- N 10-12 in each group.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 7G is a bar graph that shows collagen deposition in the aortic wall of ApoE _/" mice transfected with scrambled (Ser) siRNA or KNU siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis is the siRNA transfected, and the y-axis is the area of collagen in percent.
- N 10-12 in each group.
- P values were obtained by a ⁇ 2 test in band by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 8B is a bar graph that shows the quantification of IFN- ⁇ , IDO, and KNU in the suprarenal aortas of ApoE _/" mice transfected with scrambled (Ser) siRNA or kynureninase (KYNU) siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- N 6-10 in each group.
- P values were obtained by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 8C is a bar graph that shows the quantification of 3-HAA and MMP2 in the suprarenal aorta of ApoE _/" mice transfected with scrambled (Ser) siRNA or kynureninase (KNU) siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis is the siRNA transfected, and the y-axis is the quantification score.
- N 6-10 in each group.
- P values were obtained by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 8E is a bar graph that shows the serum concentration of Trp detected by HPLC in
- P values were obtained by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 8F is a bar graph that shows the serum concentration of 3-HAA detected by HPLC in ApoE _/" mice transfected with scrambled (Ser) siRNA or kynureninase (KNU) siRNA followed by infusion with Angll (1000 ng/min per kg) for 4 weeks.
- the x-axis is the siRNA transfected, and the y-axis is the micromolar serum concentration of 3-HAA.
- N 6-10 in each group.
- P values were obtained by a one-way ANOVA with a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 9A is an immunoblot that shows detection of IDO and GAPDH proteins in cultured HASMC that were incubated with 100 ⁇ IFN- ⁇ for the indicated time. 3 independent experiments were performed for all data.
- FIG. 9B is a line graph that shows the Trp and Kyn levels as detected by HPLC in cultured HASMC that were incubated with 100 ⁇ IFN- ⁇ for the indicated time.
- the x-axis shows time in hours, and the y-axis shows micromolar concentration. 3 independent experiments were performed for all data.
- the P values were obtained by a one-way ANOVA plus a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 9C is an immunoblot that shows detected of Pro-MMP2, Trp, and Kyn proteins in cultured HASMC transfected with control siRNA or IDO siRNA treated with or without IFN- ⁇ for 48 hours. 3 independent experiments were performed for all data.
- FIG. 9D is a bar graph that shows Trp and Kyn levels as detected by HPLC in cultured HASMC transfected with control siRNA or IDO siRNA treated with or without IFN- ⁇ for 48 hours.
- the x-axis shows administration of IDO siRNA and IFN- ⁇
- the y-axis shows micromolar concentration. 3 independent experiments were performed for all data. * P ⁇ 0.01 vs control siRNA without IFN-y treatment, *P ⁇ 0.01 vs control siRNA with IFN-y treatment.
- the P values were obtained by a one-way ANOVA plus a post hoc analysis using Bonferroni's multiple comparisons test. The error bars are standard error of the mean.
- FIG. 10A is an immunoblot that shows detection of Pro-MMP2 and GAPDH in cultured HASMC that were incubated with the indicated concentrations of Trp for 48 hours.
- FIG. 10B is an immunoblot that shows detection of Pro-MMP2, IDO, and GAPDH proteins in cultured HASMC that were either untreated (control) or treated with IFN- ⁇ combined with the indicated concentrations of exogenous Trp for 48 hours, and a bar graph that shows the Trp and Kyn levels in the culture medium as detected by HPLC.
- the x-axis of the bar graph shows the micromolar concentration of Trp administered with or with IFN- ⁇
- the y-axis of the bar graph shows the micromolar concentration of Trp and Kyn.
- the error bars are standard error of the mean.
- FIG. IOC is an immunoblot that shows detected of Pro-MMP2, IDO, and beta-actin in cultured HASMC transfected with control siRNA or IDO siRNA that were treated with vehicle (control) or IFN- ⁇ with or without addition of 50 ⁇ Trp for 48 hours, and a bar graph that shows the Trp and Kyn levels in the culture medium as detected by HPLC.
- the x-axis of the bar graph shows administration of IFN- ⁇ , IDO siRNA, and Trp
- the y-axis of the bar graph shows micromolar concentration of Trp and Kyn.
- the error bars are standard error of the mean.
- FIG. 10D is an immunoblot that shows detected Pro-MMPS, IDO, and beta-actin in cultured HASMC transfected with control siRNA or IDO siRNA that were treated with vehicle (control) or IFN- ⁇ with or without addition of 100 ⁇ Trp for 48 hours, and a bar graph that shows the Trp and Kyn levels in the culture medium as detected by HPLC.
- the x-axis of the bar graph shows administration of IFN- ⁇ , IDO siRNA, and Trp, and the y-axis shows micromolar concentration of Trp and Kyn.
- the error bars are standard error of the mean.
- FIG. 10E is an immunoblot that shows detection of Pro-MMP2 and GAPDH in cultured HASMC that were incubated with the indicated concentrations of Trp for 48 hours.
- FIG. 11 is a proposed scheme for Angll-induced AAA formation via 3-hydroxyanthranilic acid (3-HAA) elevation in mice.
- Angll binds to its receptor in vascular smooth muscle cells to promote secretion of IFN- ⁇ , which powerfully activates the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism.
- Highly-induced indoleamine-2,3-di oxygenase (IDO) initially catalyzes Trp to Kyn, which is further metabolized to 3-HAA by intensely upregulated kynureninase (KYNU) expression.
- IDO indoleamine-2,3-di oxygenase
- Trp-derived 3-HAA induces the phosphorylation of the main MMP2 transcriptional factor Elkl, which triggers MMP2 overexpression and subsequent MMP2 secretion to outside of cells and cleavage to activated MMP2 by MT1-MMP.
- active MMP2 degrades extracellular matrix resulting in the loss of the resistance of the vascular wall to blood flow and consequent formation of an aortic aneurysm.
- FIG. 12 is a western blot that shows detection of indoleamine-pyrrole 2,3 -di oxygenase, L- kynurenase, p-ELK-1, ELK-1, MMP2, GAPDH, and actin in human AAA tissues and their control adjacent aortic section without an aneurysm that were obtained from patients undergoing open surgery.
- FIG. 13 A is a bar graph that shows densitometric analysis of the western blot shown in
- FIG. 12 of 2,3 -di oxygenase in relation to GAPDH in control tissue and AAA tissue obtained from patients undergoing open surgery.
- the x-axis shows the sampled tissue, and the y-axis shows the relative intensity. *p ⁇ 0.01.
- the error bars are standard error of the mean.
- FIG. 13B is a bar graph that shows densitometric analysis of the western blot shown in FIG. 12 of L-Kyn in relation to GAPDH in control tissue and AAA tissue obtained from patients undergoing open surgery.
- the x-axis shows the sampled tissue, and the y-axis shows the relative intensity. *p ⁇ 0.01.
- the error bars are standard error of the mean.
- FIG. 13C is a bar graph that shows densitometric analysis of the western blot shown in FIG. 12 of ELK-1 in relation to GAPDH in control tissue and AAA tissue obtained from patients undergoing open surgery.
- the x-axis shows the sampled tissue, and the y-axis shows the relative intensity. *p ⁇ 0.01.
- the error bars are standard error of the mean.
- FIG. 13D is a bar graph that shows densitometric analysis of the western blot shown in FIG. 12 of P-ELK-1 in relation to GAPDH in control tissue and AAA tissue obtained from patients undergoing open surgery.
- the x-axis shows the sampled tissue, and the y-axis shows the relative intensity. *p ⁇ 0.01.
- the error bars are the standard error of the mean.
- FIG. 13E is a bar graph that shows densitometric analysis of the western blot shown in FIG. 12 of MMP-2 in relation to GAPDH in control tissue and AAA tissue obtained from patients undergoing open surgery.
- the x-axis shows the sampled tissue, and the y-axis shows the relative intensity. *p ⁇ 0.01.
- the error bars are the standard error of the mean.
- FIG. 14 shows representative immunohistochemical staining of kyureninase in human aortic sections with or without AAA.
- FIG. 15 shows representative immunohistochemical staining of indoleamine-pyrrole 2,3- dioxygenase (IDO) in human aortic sections with or without AAA.
- IDO indoleamine-pyrrole 2,3- dioxygenase
- FIG. 16 show representative immunohistochemical staining of 2-hydroxyanthranilic acid (3-HAA) in human aortic sections with or without AAA.
- Human AAA samples had stronger anti- 3-HAA staining than adjacent nonaneurysmal aortic sections.
- the x-axis shows the analyzed group, and the y-axis shows the micromolar plasma concentration of 3-HAA.
- Human AAA samples exhibited higher concentrations of plasma 3-HAAA than those in non-AAA patients.
- the error bars are standard error of the mean.
- FIG. 18 are representative photographs showing the macroscopic features of Ang-II induced aneurysms in four groups of ApoE _/" mice: vehicle treated; vehicle +acipimox treated; Angll treated; and Angll + acipimox treated.
- FIG. 19A is a bar graph that shows AAA incidence in four groups of ApoE " ' " mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the x-axis shows the group of mice, and the y-axis shows the AAA incidence in percent.
- FIG. 19B is a scatter plot that shows maximal abdominal aortic diameter in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the x-axis shows the group of mice, and y-axis shows the maximal abdominal aortic diameter in millimeters. * P ⁇ 0.05 versus vehicle. # P ⁇ 0.05 versus Angll. The error bars are standard error of the mean.
- FIG. 19C is a bar graph that shows the aorta weight to body weight ratio in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the x-axis shows the group of mice, and the y-axis shows the aorta weight to body weight ration. * P ⁇ 0.05 versus vehicle. # P ⁇ 0.05 versus Angll.
- the error bars are standard error of the mean.
- FIG. 20 is a graph that shows the survival rate in days in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the x- axis is treatment time in days, and the y-axis is survival rate in percent.
- FIG. 21 depicts representative images of the mice abdominal aorta from four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- FIG. 22A is a bar graph that shows the abdominal diastolic aortic diameter as measured by ultrasound in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the error bars are standard error of the mean.
- FIG. 22B is a bar graph that shows the abdominal systolic aortic diameter as measured by ultrasound in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the error bars are standard error of the mean.
- FIG. 23 A is a bar graph that shows the speed of propagation (PWV) in the abdominal aorta (mm/s) as measured in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; and Angll + acipimox treated.
- the x-axis shows the group of mice, and the y-axis shows the PWV of the abdominal aorta in millimeters per second.
- the error bars are standard error of the mean.
- FIG. 23B is a bar graph that shows the speed of propagation (PWV) in the carotid artery (mm/s) as measured in four groups of ApoE _/" mice: vehicle treated; vehicle + acipimox treated; Angll treated; Angll + acipimox treated.
- the x-axis shows the group of mice, and the y-axis shows the PWV of the carotid artery in millimeters per second.
- the error bars are standard error of the mean.
- FIG. 24A is a bar graph that shows the increase in the development of AAA formation in two groups of ApoE _/" mice infused with Angll for four weeks and then treated with either vehicle or acipimox for six weeks.
- the x-axis is the treatment, and the y-axis is the increase in AAA incidence in percent.
- the x-axis shows the treatment, and the y-axis shows the increase in abdominal aorta diameter.
- FIG. 25 is a schematic drawing depicting the major enzymes and catabolites in tryptophan metabolism. Tryptophan is metabolized via two major pathways: the kynurenine pathway and the serotonin/melatonin pathway.
- FIG. 26B is a scatter plot that shows the abdominal aortic diameter of mice treated with Angll (1.44 mg/kg/day) for 14 days, followed by infusion with vehicle or 0.1% acipomox for 6 weeks.
- the x-axis shows the treatment, and the y-axis shows the abdominal aortic diameter in millimeters.
- N 21. * P ⁇ 0.01 versus vehicle.
- the error bars are standard error of the mean.
- FIG. 26C is a line graph that shows the change over time in abdominal aortic diameter in mice treated with Angll (1.44 mg/kg/day) for 14 days, followed by infusion with vehicle or 0.1% acipimox for 6 weeks.
- the x-axis shows time in days, and the y-axis shows the abdominal aortic diameter in millimeters.
- the error bars are standard error of the mean.
- FIG. 27A is a bar graph that shows the incidence of TAA in one of four groups of ApoE " ' " mice: vehicle treated; vehicle + acipimox treated; Angll treated; and AngII+ acipimox treated.
- the x-axis show the group of mice, and the y-axis shows the incidence of TAA in percent.
- FIG. 27B is a scatter plot that shows the maximal thoracic aortic diameter in one of four groups of ApoE _/" mice: vehicle treated; vehicle+acipimox treated; Angll treated; and Angll+acipimox treated.
- the x-axis shows the group of mice, and the y-axis shows the maximal thoracic aortic diameter in millimeters. * P ⁇ 0.05 versus vehicle. *P ⁇ 0.05 versus Angll.
- the error bars are standard error of the mean.
- FIG. 28 is a bar graph that shows the density of 3-HAA as determined by immunohistochemical staining of human aortic sections with or without AAA.
- the x-axis shows the patient group, and the y-axis shows the 3-HAA density as the fold of the control group. *P ⁇ 0.01 versus the control.
- the error bars are standard error of the mean.
- FIG. 29 is a scatter plot that shows the relationship between aorta diameter and 3-HAA level in aneurysm positive mice.
- the x-axis shows the nanomolar 3-HAA level.
- FIG. 30 depicts representative images of abdominal aorta from five groups of ApoE _/" mice: vehicle (saline) treated; Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- FIG. 31 A is a bar graph that shows the incidence of AAA in five groups of ApoE _/" mice: vehicle (saline) treated; Angll treated; Angll+OMBA treated; Angll+NBA treated; and
- Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows AAA incidence in percent. P values were obtained using the chi-square test.
- FIG. 3 IB is a bar graph that shows the aortic weight to body weight ratio in five groups of
- ApoE _/ mice vehicle (saline) treated; Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows the aortic weight to body weight ratio.
- P values were obtained using one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparison's test. Error bars represent standard error of the mean.
- FIG. 31C is a bar graph that shows the maximal abdominal aortic diameter in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- vehicle saline treated
- Angll treated Angll+OMBA treated
- Angll+NBA Angll+NBA treated
- Angll+IMT the maximal abdominal aortic diameter in millimeters.
- P values were obtained using one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparison's test. Error bars represent standard error of the mean.
- FIG. 32A is a scatter plot that shows the serum tryptophan concentration in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+ BA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum tryptophan concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, * ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 32B is a scatter plot that shows the serum kynurenine concentration in five groups of of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum kynurenine concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni' s multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, * ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 32C is a scatter plot that shows the serum 3HAA concentration in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum 3HAA concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, * ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 32D is a scatter plot that shows the serum 3HK concentration in five groups of ApoE " mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum 3HK concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, # P ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 32D is a scatter plot that shows the serum 3HK concentration in five groups of ApoE " mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT
- 32E is a scatter plot that shows the serum kynurenic acid concentration in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum kynurenic concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni' s multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, *P ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 32F is a scatter plot that shows the serum anthranilic acid concentration in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows micromolar serum kynurenic concentration.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni' s multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, * ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 33 A is a scatter plot that shows the serum kynurenine/tryptophan ratio in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows the serum kynurenine/tryptophan ratio.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, # P ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 33B is a scatter plot that shows the serum kynurenic acid/try ptophan ratio in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows the serum kynurenic acid/tryptophan ratio.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni' s multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, * ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 33C is a scatter plot that shows the serum anthranilic acid/tryptophan ratio in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows the serum anthranilic acid/tryptophan ratio.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, # P ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 33D is a scatter plot that shows the serum 3HAA/tryptophan ratio in five groups of
- ApoE _/ mice vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+ BA treated; and Angll+IMT treated.
- the x-axis shows the group of mice, and the y-axis shows the serum 3HAA/tryptophan ratio.
- P values were obtained by a one-way ANOVA with a post-hoc analysis using Bonferroni's multiple comparisons test. *P ⁇ 0.01 for saline vs. Ang. II infused mice, # P ⁇ 0.01 for Angll vs. Angll-infused inhibitor treated mice.
- FIG. 34A is an immunoblot showing the expression of HAOO, Kynureninase, KMO, and IDO in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- FIG. 34B is a zymogram that shows the levels of MMP9, MMP2, and cleaved MMP2 in five groups of ApoE _/" mice: vehicle (saline treated); Angll treated; Angll+OMBA treated; Angll+NBA treated; and Angll+IMT treated.
- FIG. 35 is a line graph that shows the percentage increase over time in abdominal aortic diameter in mice treated with Angll (1.44 mg/kg/day) for 14 days, followed by infusion with vehicle or 0.1% acipimox for 6 weeks.
- the x-axis shows time in days, and the y-axis shows the aortic diameter increase in percent.
- the error bars are standard error of the mean.
- the x-axis is the group of mice, and the y-axis is AAA incidence in percent.
- the x-axis is the group of mice, and the y-axis is maximal abdominal aortic diameter in millimeters.
- FIG. 37A shows representative immunohistochemical staining for IDO and KYNU in aortic cross sections of vehicle (saline) treated ApoE _/" mice.
- FIG. 37B shows representative immunohistochemical staining for IDO and KYNU in aortic cross sections of Angll treated ApoE _/" mice.
- FIG. 37C shows representative immunohistochemical staining for IDO and KYNU in aortic cross sections of acipimox treated ApoE _/" mice.
- FIG. 37D shows representative immunohistochemical staining for IDO and KYNU in aortic cross sections of Angll+acipimox treated ApoE _/" mice.
- FIG. 38 is an immunoblot showing the expression of Kynureninase and IDO in five groups of ApoE _/" mice: vehicle (saline) treated; acipimox treated; Angll treated; and Angll+acipimox treated. GAPDH was used as a standard.
- Kynurenine (Kyn) pathway enzymes and/or metabolites refers to the enzymes and metabolites associated with the degradation of tryptophan in the kynurenine pathway.
- Kynurenine (Kyn) pathway enzymes and/or metabolites include indoleamine-2,3-dioxygenase- 1 (IDOl), indoleamine-2,3-dioxygenase-2 (ID02), tryptophan 2,3 -di oxygenase (TDO), N- formylkynurenine, formamidase, kynurenine (Kyn), kynurenine amino-transferase (KAT), kynureninase (KYNU), kynurenic acid (KA), anthranilic acid (AA), kynurenine-3- monooxygenase (KMO), 3 -hydroxy kynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), xanthurenic acid (XA), 2-amino-3-carboxymuconate semialdehyde, 2-aminomuconic acid semialdehyde, picolinic acid
- a “patient” or “host” or “subject” is a human or non-human animal in need of detection and/or treatment of an aneurysm, for example an abdominal aortic aneurysm (AAA), a thoracic aortic aneurysm (TAA), or a cerebral aneurysm (CA).
- AAA abdominal aortic aneurysm
- TAA thoracic aortic aneurysm
- CA cerebral aneurysm
- the subject is a human.
- a “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird and the like.
- sample can include any bodily fluid or tissue sample that may contain a metabolite, RNA, or a protein associated with the Kyn pathway to be analyzed as described herein.
- sample or sample from the subject can be used generally to refer to a sample or any type which contains products that are to be evaluated by the present method, including but not limited to, a sample of isolated cells, a tissue sample, and/or a bodily fluid sample.
- the sample may comprise blood, plasma, or serum.
- an "effective amount" of a compound or combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or prevention, reduction, or dimunition of the disease itself.
- salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with subjects (e.g., human subjects) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the presently disclosed subject matter.
- salt refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the presently disclosed subject matter.
- salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
- Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
- Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like.
- Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
- organic acids such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like.
- Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
- Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. "Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a pharmaceutically acceptable carrier or pharmaceutically acceptable excipient.
- a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.
- the term "prodrug” means a compound which when administered to a host in vivo is converted into the parent drug.
- parent drug means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
- Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
- Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
- Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
- acipimox includes desired isotopic substitutions of atoms, at amounts above the natural abundance of the isotope, i.e., enriched.
- Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
- isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures.
- isotopes of carbon e.g., 13 C and 14 C, may be used.
- a preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug.
- the deuterium can be bound in a location of bond breakage during metabolism (an a- deuterium kinetic isotope effect) or next to or near the site of bond breakage (a ⁇ -deuterium kinetic isotope effect).
- substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
- Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond.
- the hydrogen atom can be any isotope of hydrogen, including protium (3 ⁇ 4), deuterium ( 2 H) and tritium ( 3 H).
- isotopically-labeled analog refers to an analog that is a “deuterated analog", a
- 13 C-labeled analog or a “deuterated/ 13 C-labeled analog.”
- deuterated analog means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium (3 ⁇ 4), is substituted by a H-isotope, i.e., deuterium ( 2 H).
- Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium.
- the isotope is 90%, 95%, or 99% or more enriched in an isotope at any location of interest. In some embodiments, it is deuterium that is 90%, 95%, or 99% enriched at a desired location.
- AAA Abdominal Aortic Aneurysm
- AAA abdominal aortic aneurysm
- ILT intraluminal thrombus
- ILT intraluminal thrombus
- Thromb Vase Biol. (2007) 27: 1259-68 Abdominal aortic aneurysms often grow slowly and usually without symptoms, making them difficult to detect.
- Abdominal aortic aneurysm risk factors include:
- Age Abdominal aortic aneurysms occur most often in people age 65 and older;
- Tobacco use is a strong risk factor for the development of an abdominal aortic aneurysm and a higher risk of rupture. The longer one has used tobacco, the greater the risk;
- Gender Men develop abdominal aortic aneurysms much more often than women do;
- Atherosclerosis the buildup of fat and other substances that can damage the lining of a blood vessel— increases the risk of an AAA;
- aneurysms People who have an aneurysm in another large blood vessel, such as the artery behind the knee or the thoracic aorta in the chest, may have a higher risk of developing an abdominal aortic aneurysm; and,
- High blood pressure may increase your risk of developing an abdominal aortic aneurysm.
- Tears in one or more of the layers of the wall of the aorta (aortic dissection) or a ruptured aortic aneurysm are the main complications of abdominal aortic aneurysms.
- a ruptured aortic aneurysm can lead to life-threatening internal bleeding.
- AAA screening, evaluation, and surveillance programs employ the use of medical imaging techniques, including for example, but not limited to, CT angiogram (CTA), ultrasound sonography (US), and magnetic resonance imaging (MRI).
- CTA CT angiogram
- US ultrasound sonography
- MRI magnetic resonance imaging
- connective tissue, collagen, elastin, and/or fibrillin are prone to the development of AAA. Because connective tissue, collagen, elastin, and fibrillin are involved in the formation of blood vessels and the structural integrity of functioning blood vessels, including the aorta, individuals with connective tissue collagen, elastin, and/or fibrillin disorders often suffer from structural abnormalities to the aorta, resulting in a predisposition to the development of AAA.
- aortic aneurysms include Marfan syndrome (MFS; caused by FBN1 mutations), Loeys-Dietz syndrome (LDS; associated with mutations in the genes TGFBR1, TGFBR2, TGFB2, and SMAD3), aneurysms-osteoarthritis syndrome (AOS; caused by SMAD3 mutations), Ehlers-Danlos syndrome, including vascular Ehlers-Danlos syndrome (EDS IV; caused by COL3 Al mutations), familial thoracic aortic aneurysm/dissection (FTAAD; associated with ACTA2, MYH11, and MYLK mutations), Shprintzen-Goldberg syndrome, cutis laxa syndrome (CL; associated with ELN and EFEMP2 mutations), aortic valve disease (AOVD1; caused by NOTCH1 mutations), arterial tortuosity syndrome (ATS; caused by SLC2A10 mutations), X-linked Alport syndrome (XLAS; caused by
- TAA Thoracic Aortic Aneurysm
- a thoracic aortic aneurysm is a weakened area in the upper part of the aorta.
- the aorta is the major blood vessel that feeds blood to the body.
- a thoracic aortic aneurysm may also be called thoracic aneurysm and aortic dissection (TAAD) because an aneurysm can lead to a tear in the artery wall (dissection) that can cause life-threatening bleeding.
- Small and slow-growing thoracic aortic aneurysms may not ever rupture, but large, fast-growing aneurysms may rupture.
- thoracic aortic aneurysms Depending on the size and growth rate of the thoracic aortic aneurysm, treatment may vary from monitoring size and progression over time to emergency surgery. Thoracic aortic aneurysms often grow slowly and usually without symptoms, making them difficult to detect. Some aneurysms will never rupture. Many start small and stay small, although many expand over time. How quickly an aortic aneurysm may grow is difficult to predict. As a thoracic aortic aneurysm grows, symptoms include: tenderness or pain in the chest, back pain, hoarseness, cough, and/or shortness of breath. Thoracic aortic aneurysm risk factors include:
- Tobacco use is a strong risk factor for the development of a thoracic aortic aneurysm and a higher risk of rupture. The longer one has used tobacco, the greater the risk;
- Gender Men develop thoracic aortic aneurysms much more often than women do;
- Atherosclerosis increases the risk of TAA
- aneurysms People who have an aneurysm in another large blood vessel, such as the artery behind the knee or the abdominal aorta in the chest, may have a higher risk of developing a thoracic aortic aneurysm; and,
- High blood pressure may increase your risk of developing a thoracic aortic aneurysm.
- Tears in one or more of the layers of the wall of the aorta (aortic dissection) or a ruptured aortic aneurysm are the main complications of thoracic aortic aneurysms.
- a ruptured aortic aneurysm can lead to life-threatening internal bleeding.
- TAA screening, evaluation, and surveillance programs employ the use of medical imaging techniques, including for example, but not limited to, chest x-ray, echocardiogram (ECG), transesophageal echocardiogram, CT angiogram (CTA), ultrasound sonography (US), magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA).
- ECG echocardiogram
- CTA CT angiogram
- US ultrasound sonography
- MRI magnetic resonance imaging
- MRA magnetic resonance angiography
- connective tissue, collagen, elastin, and/or fibrillin are prone to the development of TAA. Because connective tissue, collagen, elastin, and fibrillin are involved in the formation of blood vessels and the structural integrity of functioning blood vessels, including the aorta, individuals with connective tissue collagen, elastin, and/or fibrillin disorders often suffer from structural abnormalities to the aorta, resulting in a predisposition to the development of TAA.
- aortic aneurysms include Marfan syndrome (MFS; caused by FBN1 mutations), Loeys-Dietz syndrome (LDS; associated with mutations in the genes TGFBR1, TGFBR2, TGFB2, and SMAD3), aneurysms-osteoarthritis syndrome (AOS; caused by SMAD3 mutations), Ehlers-Danlos syndrome, including vascular Ehlers-Danlos syndrome (EDS IV; caused by COL3 Al mutations), familial thoracic aortic aneurysm/dissection (FTAAD; associated with ACTA2, MYH11, and MYLK mutations), Shprintzen-Goldberg syndrome, cutis laxa syndrome (CL; associated with ELN and EFEMP2 mutations), aortic valve disease (AOVD1; caused by NOTCH1 mutations), arterial tortuosity syndrome (ATS; caused by SLC2A10 mutations), X-linked Alport syndrome (XLAS; caused by
- a cerebral aneurysm is a bulge or ballooning in a blood vessel in the brain. Cerebral aneurysms most commonly occur in the anterior communicating artery, posterior communicating artery, anterior cerebral artery, middle cerebral artery, posterior cerebral artery, internal carotid artery, or the tip of the basilar artery.
- a brain aneurysm can leak or rupture, causing bleeding into the brain (hemorrhagic stroke). Most often a ruptured brain aneurysm occurs in the space between the brain and the thin tissues covering the brain. This type of hemorrhagic stroke is called a subarachnoid hemorrhage.
- a ruptured aneurysm quickly becomes life-threatening and requires prompt medical treatment. Most brain aneurysms, however, don't rupture, create health problems, or cause symptoms. Such aneurysms are often detected during tests for other conditions.
- Common signs and symptoms of a ruptured aneurysm include: sudden, extremely severe headache, nausea and vomiting, stiff neck, blurred or double vision, sensitivity to light, seizure, a drooping eyelid, loss of consciousness, and/or confusion.
- Brain aneurysms are more common in adults than in children and more common in women than in men. Some of these risk factors develop over time; others are present at birth. Risk factors that develop over time include: older age, cigarette smoking, high blood pressure (hypertension), drug abuse, particularly the use of cocaine, and heavy alcohol consumption. Some types of aneurysms may occur after a head injury (dissecting aneurysm) or from certain blood infections (mycotic aneurysm).
- Diagnostic tests for CA include: computerized tomography (CT), CT angiography, cerebrospinal fluid test, magnetic resonance imaging (MRI) angiography, or a cerebral angiogram.
- CT computerized tomography
- MRI magnetic resonance imaging
- cerebral angiogram a cerebral angiogram
- the Kyn pathway is the major route for the metabolism of the essential amino acid tryptophan (Trp).
- Enzymes and metabolites associated with the Kyn pathway include indoleamine-2,3-di oxygenase- 1 (IDOl), indoleamine-2,3-dioxygenase-2 (ID02), tryptophan 2,3- dioxygenase (TDO), N-formylkynurenine, formamidase, kynurenine (Kyn), kynurenine amino- transferase (KAT), kynureninase (KYNU), kynurenic acid (KA), anthranilic acid (AA), kynurenine-3-monooxygenase (KMO), 3 -hydroxy kynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), xanthurenic acid (XA), 2-amino-3-carboxymuconate semialdehyde,
- Trp is constitutively oxidized by tryptophan 2,3 -di oxygenase in liver cells. In other cell types, Trp is catalyzed by an alternative inducible indoleamine-pyrrole 2,3-dioxygenase-l (IDOl) under certain pathophysiological conditions.
- IDOl inducible indoleamine-pyrrole 2,3-dioxygenase-l
- kynureninase directly catalyzes the hydrolysis of Kyn or 3 -hydroxy kynurenine (3-HK) to form anthranilic acid (AA) or 3-hydroxyanthranilic acid (3-HAA), respectively (Figure 25).
- Kynureninase is an endothelium- derived relaxing factor produced during inflammation. Nat Med.
- IDOl is a potential novel contributor to vessel relaxation in systemic infections (Hofmann F. Ido brings down the pressure in systemic inflammation. Nat Med.
- kynurenine pathway a cascade of enzymatic steps containing several biologically active compounds. Metabolites of this pathway, collectively termed 'kynurenines', have been shown to be involved in many diverse physiological and pathological processes.
- Kynurenine pathway inhibitors for use in the methods described herein include, but are not limited to, indoleamine 2,3- di oxygenase- 1 (IDOl) inhibitors, tryptophan 2,3, di oxygenase (TDOl) inhibitors, dual IDOl/TDOl inhibitors, kynurenine 3-monooxygenase (KMO) inhibitors, and kynureninase (KYNU) inhibitors.
- IDOl indoleamine 2,3- di oxygenase- 1
- TDOl tryptophan 2,3, di oxygenase
- KMO kynurenine 3-monooxygenase
- KYNU kynureninase
- a subject determined to have an excessive 3-HAA level, or a subject with a formed aneurysm, or at risk for forming an aneurysm is administered an 3-HAO up-regulator, which induces the expression of 3-HAO, providing a mechanism for the degradation of formed 3-HAA.
- the inhibition of KNYU provides a particular effective method of inhibiting the formation of 3-HAA.
- the KYN pathway inhibitor administered to a subject to inhibit the formation of or delay the progression of an aneurysm is a KNYU inhibitor.
- the KYN inhibitor for administration is a KMO.
- the KYN inhibitor is an IDOl inhibitor.
- the KYN inhibitor administered is not an IDOl inhibitor.
- the subject is administered an effective amount of a 3-HAO up- regulator.
- Kynurenine pathway inhibitors are known in the art and include, but are not limited to, those described further below.
- a kynureninase (KYNU) inhibitor is administered to a subject having a formed aneurysm or at risk for developing an aneurysm.
- a KYNU inhibitor is administered to a subject with an elevated 3-HAA level as determined by the methods described herein.
- KYNU inhibitors have shown a more efficient inhibition of 3-HAA formation and, accordingly, aneurysm formation and progression than upstream KYN inhibitors such as IDOl and KMO inhibitors.
- KYNU inhibitors are known in the art and include, but are not limited to, those described further below.
- 2-Amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid is a KYNU inhibitor having the chemical formula:
- KYNU inhibitors are described in Dua, R. K. et al. "S-Aryl-L-cy stein S,S- Dioxides: Design, Synthesis, and Evaluation of a New Class of Inhibitors of Kynureninase" J. Am. Chem. Soc. 1993, 115: 1264-1270, incorporated herein by reference.
- a particularly useful KYNU inhibitor of the series is the compound having the chemical formula:
- a series of KYNU inhibitors for example a compound of the chemical formula
- Benserazide is a KYNU inhibitor and aromatic L-amino acid decarboxylase/DOPA decarboxylase inhibitor having the chemical formula:
- NBA m-Nitrobenzoylalanine
- KMO kyurenine-3-monooxygenase
- KYNU can also be inhibited by the administration of, for example, an siRNA, for example kynureninase siRNA (lnvitrogen, 4457308).
- siRNA for example kynureninase siRNA (lnvitrogen, 4457308).
- KMO Kynurenine-3-monooxygenase
- a kynurenine-3-monooxygenase (KMO) inhibitor is administered to a subject having a formed aneurysm or at risk for developing an aneurysm.
- a KMO inhibitor is administered to a subject with an elevated 3-HAA level as determined by the methods described herein.
- KMO inhibitors are known in the art and include, but are not limited to, those described further below.
- GSK180 oxazolidinone
- KMO kynurenine-3- monooxygenase
- GSK180 is described in U.S. Patent App. No. US20170349577 entitled "3-(6-Alkoxy-5- chlorobenzo[D]isoxazol-3-yl)propanoic acid useful as kynurenine monooxygenase inhibitors," incorporated herein by reference.
- KMO kyurenine-3 -monooxygenase
- CHDI-340246 is a potent and selective inhibitor of kynurenine 3 -monooxygenase (KMO) with the chemical formula:
- CHDI-340246 is described in Beaumont, V. et al. "The novel KMO inhibitor CHDI-340246 leads to restoration of electrophysiological alterations in mouse models of Huntington's disease” Exp. Neurol. 2016, 282:99-118, the entirety of which is incorporated herein by reference.
- Des-amino FCE 28833 is an inhibitor of kynurenine 3 -monooxygenase (KMO) with the chemical formula:
- Des-amino FCE 28833 is described in Speciale, C. et al. "Kynurenic Acid-Enhancing and Anti-ischemic Effects of the Potent Kynurenine 3-Hydroxylase Inhibitor FCE 28833 in Rodents" Adv. Exp. Med. Biol. 1996, 398:221-227, the entirety of which is incorporated herein by reference.
- UPF 648 is a kynurenine 3-monooxygenase (KMO) inhibitor with the chemical formula:
- Ro-61-8048 is an inhibitor of kynurenine 3-monooxygenase with the chemical formula:
- a indoleamine 2,3-dioxygenase-l (IDOl) inhibitor is administered to a subject with an elevated 3-HAA level as determined by the methods described herein.
- IDOl inhibitors are known in the art and include, but are not limited to, those described further below.
- Indoximod (1-methyl-D-tiyptophan) is an orally available small molecule targeting Indoleamine 2,3-dioxygenase-l (IDOl) having the chemical formula:
- NLG919 (Navoximod), is an orally available inhibitor of indoleamine 2,3-dioxygenase 1 (IDOl) having the chemical formula:
- NLG802 (NewLink Genetics Corporation) is an orally available prodrug of indoximod, a small molecule targeting the IDOl Pathway.
- Epacadostat (l,2,5-Oxadiazole-3-carboximidamide, 4-((2-((Aminosulfonyl)amino) ethyl) amino)-N-(3-bromo-4-fluorophenyl)-N' -hydroxy-, (C(Z))-), is an orally available hydroxyamidine and inhibitor of indoleamine 2,3-dioxygenase (IDOl) with the chemical formula:
- Epacadostat is found in U.S. Patent No. 8,088,803 entitled "1,2,5-Oxadiazoles as inhibitors of indoleamine 2,3,-dioxygenase," incorporated herein by reference.
- BMS-986205 (F- 001287) is an orally available inhibitor of indoleamine 2,3 -di oxygenase (IDOl) with the chemical formula:
- BMS-986205 The structure of BMS-986205 is found in U.S. Patent No. 9,598422 entitled “Immunoregulatory Agents,” incorporated herein by reference.
- PF-06840003 is a highly selective orally bioavailable IDO-1 inhibitor with the chemical formula:
- PF-06840003 The structure of PF-06840003 is found in U.S. Patent No. 9,603,836 entitled "Pyrrolidine- 2, 5-Dione Derivatives, Pharmaceutical Compositions and Methods for use as IDOl inhibitors," incorporated herein by reference.
- IDOl indoleamine 2,3 -di oxygenase
- HTI-1090 SHR9146 is an orally bioavailable, highly potent, novel small-molecule IDOl/TDO dual inhibitor.
- HTI-1090 is disclosed in WO2016/169421 entitled “Imidazo Isoindole Derivative, Preparation Method Therefore and Medical Use Thereof,” incorporated herein by reference.
- IOM2983 Merck
- Related dual IDO/TDO inhibitors include IOM2983 (Merck) and related compounds disclosed in US2014/0221354, US20160367564, US20170107178, US20170267668, and WO/2017/189386A1, all incorporated herein by reference.
- RG-70099/CRD1152 (Roche/Curadev) is an orally bioavailable small molecule dual indoleamine 2,3 -di oxygenase 1 (IDOl) and tryptophan 2,3-dioxygenase (IDO:TDO) inhibitor described in U.S. Patent No. 9,815,811 entitled “Inhibitors of the kynurenine pathway,” incorporated herein by reference.
- a 3 -Hydroxyanthranilate-3,4-di oxygenase (3-HAO) upregulator is administered to a subject having a formed aneurysm or at risk for developing an aneurysm.
- a 3-HAO upregulator is administered to a subject with an elevated 3-HAA level as determined by the methods described herein.
- 3-HAO is a non-heme extradiol dioxygenase belonging to the cupin superfamily of proteins and is dependent upon Fe 2+ for activity.
- any agent that increases Fe 2+ status for example lipid peroxides or ascorbic acid, will increase the activity of this enzyme.
- the 3-HAO upregulator is selected from an iron supplement, ascorbic acid, and a combination thereof.
- acipimox is administered to a subject having a formed aneurysm or at risk for developing an aneurysm.
- acipimox is administered to a subject with an elevated 3-HAA level as determined by the methods described herein.
- Acipimox is a niacin derivative and nicotinic acid analog with activity as a hypolipidemic agent having the chemical formula: Other Active Agents
- a method of treating an aneurysm in a subject with an elevated 3-HAA level as determined by the methods described herein comprising administering to the subject a compound selected from fenofibrate, telmisartan, 5-((7-Cl-lH-indol-3-yl)methyl)-3- methylimidazolidine-2,4-dione) (7-Cl-O-Nec-l), a ⁇ -blocker, angiotensin converting enzyme inhibitor (ACEI), angiotensin II type I receptor (AGTR1) blocker (ARBs), statin, tetracycline/macrolide, ERK inhibitor, losartan, pravastatin, ⁇ -blocker atenolol, the ACEI perindopril, the calcium channel blocker (CCB) verapamil, roxithromycin, ethinyl estradiol, nebivolol, and doxycycline
- ACEI angio
- provided herein is a method of treating a subject with a formed aneurysm, or who is at risk of developing an aneurysm, comprising administering a KNYU inhibitor, a KMO inhibitor, or acipimox in combination with an additional agent.
- the additional agent is selected from fenofibrate, telmisartan, 5-((7-Cl-lH-indol-3-yl)methyl)-3- methylimidazolidine-2,4-dione) (7-Cl-O-Nec-l), a ⁇ -blocker, angiotensin converting enzyme inhibitor (ACEI), angiotensin II type I receptor (AGTR1) blocker (ARBs), statin, tetracycline/macrolide, ERK inhibitor, losartan, pravastatin, ⁇ -blocker atenolol, the ACEI perindopril, the calcium channel blocker (CCB) verapamil, roxithromycin, ethinyl estradiol, nebivolol, and doxycycline.
- ACEI angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type I receptor
- statin tetracycline/macrolide
- AAA abdominal aortic aneurysm
- TAA thoracic aortic aneurysm
- CA cerebral aneurysm
- the presence or expansion of an aneurysm in a subject can be determined, for example, by analyzing the level of one or more Kyn Pathway enzymes and/or metabolites in a sample from a subject and comparing the subject's level of one or more Kyn enzymes and/or metabolites to a range of standardized Kyn enzyme and/or metabolite levels derived from subjects without an aneurysm, subjects with an aneurysm, and/or subjects with a dissected aneurysm.
- a method of screening for the presence of an aneurysm in a subject comprising: i. determining the level of one or more kynurenine (Kyn) pathway enzymes and/or metabolites present in a sample from the subject; and
- aneurysm range b. with an aneurysm
- the one or more Kyn pathway enzymes and/or metabolites is selected from kynurenine (KYN), kynurenine acid (KYNA), 3 -hydroxy kynurenine (3-HK), xanthurenic acid (XA), anthranilic acid (AA), picolinic acid (PIC), quinolinic acid (QUIN), 3- hydroxyanthranilic acid (3-HAA), nicotinic acid (NA), nicotinamide (NAM), Nl- methylnicotinamide (mNAM), kynuruenine-3-monooxygenase (KMO), kynurenine aminotransferase (KAT), tryptophan 2,3 dioxygenase (TDO), ind
- the Kyn pathway enzyme or metabolite is 3-HAA. In one embodiment, the one or more Kyn pathway enzymes and/or metabolites includes at least 3-HAA. In one embodiment, the one or more Kyn pathway enzymes and/or metabolites includes 3-HAA and one or more of KYN, 3-HK, XA, AA, KYNA, PIC, NA, NAM, mNAM, KAT, KMO, IDO, TDO, and QUIN. In one embodiment, the aneurysm is an AAA. In one embodiment, the aneurysm is a TAA. In one embodiment, the aneurysm is a CA. In one embodiment, the sample from the subject is blood, plasma, or serum.
- the method further comprises confirming the presence of an aneurysm through the use of a medical imaging technique, for example through for example, but not limited to, chest x-ray, echocardiogram (ECG), transesophageal echocardiogram, CT angiogram (CTA), ultrasound sonograph, magnetic resonance imaging (MRI), computerized tomography (CT), CT angiography, cerebrospinal fluid test, or a cerebral angiogram.
- a medical imaging technique for example through for example, but not limited to, chest x-ray, echocardiogram (ECG), transesophageal echocardiogram, CT angiogram (CTA), ultrasound sonograph, magnetic resonance imaging (MRI), computerized tomography (CT), CT angiography, cerebrospinal fluid test, or a cerebral angiogram.
- ECG echocardiogram
- CTA CT angiogram
- MRI magnetic resonance imaging
- CT computerized tomography
- CT CT angiography
- cerebrospinal fluid test or a cerebral angiogram.
- a Kyn pathway metabolite for example, kynurenine (KYN), kynurenic acid (KYNA), 3 -hydroxy kynurenine (3-HK), xanthurenic acid (XA), anthranilic acid (AA), picolinic acid (PIC), quinolinic acid (QUIN), 3-hydroxyanthranilic acid (3-HAA), nicotinic acid (NA), nicotinamide (NAM), or Nl-methylnicotinamide (mNAM), is analyzed to determine the presence of an aneurysm.
- the metabolite 3-HAA is analyzed, as described herein, to determine the presence of an aneurysm.
- the metabolite 3-HAA is analyzed, as described herein, in addition to one or more additional Kyn metabolites selected from kynurenine (KYN), kynurenic acid (KYNA), 3 -hydroxy kynurenine (3-HK), xanthurenic acid (XA), anthranilic acid (AA), picolinic acid (PIC), quinolinic acid (QUIN), nicotinic acid (NA), nicotinamide (NAM), or Nl-methylnicotinamide (mNAM), to determine the presence of an aneurysm.
- one or more Kyn pathway metabolites are analyzed to determine the presence of AAA.
- one or more Kyn pathway metabolites are analyzed to determine the presence of TAA.
- one or more Kyn pathway metabolites are analyzed to determine the presence of CA.
- the Kyn enzyme and/or metabolite is selected from IDO-1, TDO, kynurenine 3-monooxygenase (KMO), kynureninase (KYNU), and 3-HAA, or a combination thereof.
- the one or more Kyn enzymes and/or metabolites includes at least 3- HAA.
- the Kyn enzyme and/or metabolite is 3-HAA.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA and IDO-1.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA and TDO.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA and KMO.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA and KYNU.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA, IDO-1, TDO, KMO and KYNU.
- the Kyn enzyme and/or metabolite analyzed is 3-HAA, IDO-1
- Methods to measure expression levels of Kyn pathway enzymes and metabolites are generally known in the art, and generally include, but are not limited to: Western blot, immunoblot, enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, microcytometry, microarray, microscopy, fluorescence activated cell sorting (FACS), liquid chromatography-mass spec (LC-MS), HPLC methods with UV detection or coulometric detection, LC-MS/MS, and flow cytometry, as well as assays based on a property of the enzyme or metabolite including but not limited to enzymatic activity or interaction with other protein partners.
- ELISA enzyme-linked immunosorbant assay
- RIA radioimmun
- Binding assays are also well known in the art.
- a BIAcore machine can be used to determine the binding constant of a complex between two proteins.
- the dissociation constant for the complex can be determined by monitoring changes in the refractive index with respect to time as buffer is passed over the chip (O'Shannessy et al., 1993, Anal. Biochem. 212:457; Schuster et al., 1993, Nature 365:343).
- suitable assays for measuring the binding of one protein to another include, for example, immunoassays such as enzyme linked immunoabsorbent assays (ELISA) and radioimmunoassays (RIA); or determination of binding by monitoring the change in the spectroscopic or optical properties of the proteins through fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR).
- ELISA enzyme linked immunoabsorbent assays
- RIA radioimmunoassays
- NMR nuclear magnetic resonance
- the Kyn pathway metabolite analyzed is 3-HAA.
- Direct measurements of 3-HAA can be measured using techniques for measuring 3-HAA concentrations known in the field as described above.
- the level of 3-HAA in a sample can be measured with various techniques including metabolite isolation, separation, and analysis by chromatographic, electrophoretic, and immunochemical techniques, for example ELISA, Western Blot, and/or PAGE gel.
- 3-HAA is measured using an anti-conjugated 3-HAA antibody, for example, a polyclonal antibody against Conjugated 3-HAA (Eagle Biosciences, IS1008).
- Western blots may be performed as described previously in Wang Q, et al., Activation of NAD(P)H Oxidase by Tryptophan-Derived 3 -Hydroxy kynurenine Accelerates Endothelial Apoptosis and Dysfunction In Vivo. Circ Res. (2014) 114:480-92.
- 3-HAA concentrations in a sample can be determined by reference to a standard curve consisting of known concentrations of a purified reference protein or metabolite.
- the 3-HAA level in a subject having, or suspected of having, an aneurysm for example AAA, TAA, or CA, is derived and compared against a standardized 3- HAA level.
- the standardized 3-HAA level is derived from a pool of samples, for example human plasma, blood, or serum, that is reflective of a 3-HAA level from a data set of individuals that do not have an aneurysm.
- the standardized 3-HAA level represents a range of 3-HAA levels from a data set of individuals that do not have an aneurysm ("normal range").
- the normal range includes a mean.
- the subject's 3-HAA level is compared to the mean of the normal range.
- an aneurysm is suspected if the subject's 3-HAA level is greater than the normal range.
- an aneurysm for example an AAA, TAA, or CA, is suspected if the subject's 3-HAA level is greater than about 1.5 times (1.5X) the mean of the normal range. In one embodiment, an aneurysm is suspected if the subject's 3-HAA level is greater than about 1.75X the mean of the normal range. In one embodiment, an aneurysm is suspected if the subject's 3- HAA level is greater than about 2. OX the mean of the normal range. In one embodiment, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.25X the mean of the normal range. In one embodiment, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.5X the mean of the normal range.
- the standardized 3-HAA level is derived from a pool of samples, for example human plasma, blood, or serum, that is reflective of a 3-HAA level from a data set of individuals having an aneurysm, for example an AAA, TAA, or CA.
- the standardized 3- HAA level comprises a range of 3-HAA levels from a data set of individuals that have AAA ("AAA range"), TAA ("TAA range"), or CA ("CA range”).
- AAA is suspected if the subject's 3-HAA level falls within the AAA range.
- TAA is suspected if the subject's 3-HAA level falls within the TAA range.
- CA is suspected if the subject's 3-HAA level falls within the CA range.
- the standardized 3-HAA level comprises a set of ranges of 3-HAA levels, wherein each set is derived from a data set of individuals that have an aneurysm with an arterial diameter of a defined size ("aneurysmal range set").
- the standardized 3-HAA level comprises a set of ranges of 3-HAA levels, wherein each set is derived from a data set of individuals that have an AAA or TAA with an aortal diameter of a defined size, for example less than about 5 cm, from about 5 cm to about 6 cm, greater than about 6 cm, etc. (“AAA or TAA range set").
- the 3-HAA level from the subject having, or suspected of having, AAA or TAA is compared to the AAA or TAA range set, wherein a 3-HAA level that falls within a particular AAA or TAA range set, for example a 3-HAA level corresponding to the AAA or TAA range set of a defined size, for example greater than about 6 cm, is indicative of the presence in the subject of an AAA or TAA having that defined diameter size.
- the standardized 3-HAA level comprises a set of ranges of 3-HAA levels, wherein each set is derived from a data set of individuals that have a CA with an arterial diameter of a defined size ("CA range set").
- the standardized 3-HAA level is derived from a pool of samples, for example human plasma, that is reflective of a 3-HAA level from a data set of individuals having a dissected aneurysm ("dissected aneurysmal range").
- the standardized 3-HAA level is derived from a pool of samples that is reflective of a 3-HAA level from a data set of individuals having a dissected AAA or TAA ("dissected AAA range").
- the standardized 3-HAA level is derived from a pool of samples that is reflective of a 3-HAA level from a data set of individuals having a dissected CA ("dissected CA range").
- a subject with a 3-HAA level within the dissected AAA or TAA range indicates the presence of an AAA or TAA at risk of dissecting. In one embodiment, a subject with a 3-HAA level within the dissected CA range indicates the presence of a CA at risk of dissecting.
- a method of determining whether an aneurysm in a subject is at risk for dissection comprising determining the level of 3-HAA present in a sample from the subject, and comparing the subject's level of 3-HAA to a range of standardized 3-HAA levels derived from individuals having a dissected aneurysm ("dissected aneurysmal range"), wherein the risk of the aneurysm dissecting is elevated if the subject's one or more 3-HAA levels fall within the dissected aneurysmal range.
- the aneurysm is an AAA, TAA, or CA.
- a method of screening for the presence of an aneurysm in a subject comprising:
- the level of 3-HAA present in a sample from the subject i. determining the level of 3-HAA present in a sample from the subject; and ii. comparing the subject's level of 3-HAA to a range of standardized 3-HAA levels derived from individuals without an aneurysm ("normal range"); wherein the presence of an aneurysm is suspected if the subject's 3-HAA level is greater than the normal range.
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 1.5 times (1.5X) the mean of the normal range.
- an aneurysm is suspected if the subject's 3-HAA level is greater than about 1.75X the mean of the normal range. In embodiments, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2. OX the mean of the normal range. In embodiments, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.25X the mean of the normal range. In embodiments, an aneurysm is suspected if the subject's 3-HAA level is greater than about 2.5X the mean of the normal range.
- the method further includes performing a medical imaging technique on the subject if the subject's 3-HAA plasma level is greater than the normal range in order to verify or exclude the presence of an aneurysm.
- a medical intervention for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth or capable of stabilizing the aneurysm, for example a compound described herein.
- the subject undergoes surgical intervention to repair the aneurysm.
- a method of screening for the presence of an aneurysm in a subject comprising:
- aneurysmal range a range of standardized 3-HAA levels derived from individuals with an aneurysm
- the aneurysm is an AAA. In embodiments, the aneurysm is a TAA. In embodiments, the aneurysm is a C A. In embodiments, the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified AAA ("AAA range"). In embodiments, the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified TAA ("TAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals with a verified CA ("CA range").
- the method further includes performing a medical imaging technique on a subject with a 3-HAA plasma level within the aneurysmal range in order to verify the presence of an aneurysm.
- the subject's 3-HAA level is determined to be within the aneurysmal range, the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm.
- a method of determining whether an aneurysm in a subject is at risk for dissection comprising:
- determining the level of 3-HAA present in a sample from the subject i. determining the level of 3-HAA present in a sample from the subject; and ii. comparing the subject's level of 3-HAA to a range of standardized 3-HAA levels derived from individuals having a dissected aneurysm ("dissected aneurysmal range");
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected AAA ("dissected AAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected TAA ("dissected TAA range").
- the subject's level of 3-HAA is compared to a range of standardized 3-HAA levels derived from individuals having a dissected CA ("dissected CA range").
- the method further includes performing a medical imaging technique on a subject with a 3-HAA plasma level within the dissected aneurysmal range in order to verify the presence of an aneurysm.
- the subject's 3-HAA level is determined to be within the dissected aneurysmal range
- the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm, for example an open surgical or endovascular aneurysm repair is performed to repair the AAA, TAA, or CA.
- a method of detecting arterial diameter expansion in an aneurysm in a subject comprising:
- determining a first level of 3-HAA present in a first sample from the subject wherein the first sample is taken at a first point in time
- determining a second level of 3-HAA present in a second sample from the subject wherein the second sample is taken at a second point in time, wherein the second point in time is after the first point in time
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the arterial diameter expansion of an AAA or TAA is an expansion of the diameter of the aorta at the site of the aneurysm ("aortic diameter expansion").
- the arterial diameter expansion of a CA is an expansion of the diameter of the anterior communicating artery, posterior communicating artery, anterior cerebral artery, middle cerebral artery, posterior cerebral artery, internal carotid artery, or the tip of the basilar artery at the site of the aneurysm.
- the method further includes performing a medical imaging technique on a subject with a second level of 3-HAA greater than the first level of 3-HAA in order to verify the presence of arterial diameter expansion in the aneurysm.
- a medical imaging technique on a subject with a second level of 3-HAA greater than the first level of 3-HAA in order to verify the presence of arterial diameter expansion in the aneurysm.
- an open surgical or endovascular aneurysm repair is performed to repair the aneurysm.
- the subject if the subject's second level of 3-HAA is greater than the first level of 3-HAA, the subject undergoes a medical intervention, for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- a medical intervention for example, the administration of a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject undergoes surgical intervention to repair the aneurysm, for example an open surgical or endovascular aneurysm repair is performed to repair the AAA, TAA, or CA.
- the sample tested is compared to standardized ranges derived using the same technique, thus accounting for potential differences and sensitivity levels across differing measuring techniques. Additionally, the sample detected may be compared to standardized ranges derived from one type of aneurysm, for example AAA, TAA, or CA, even though there may be overlap between the ranges for different types of aneurysms.
- Kyn pathway metabolite levels in human populations have been previously described, see for example, Midttun et al., Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations. Am J Clin Nutr 2017; 105: 1314-26.
- the mean normal range of 3-HAA in a plasma sample of 250 subjects as measured by FIPLC-LC-MS was about .14 ⁇ /L.
- the method further includes determining the level of one or more additional markers selected from a marker related to thrombus remodeling, a marker associated with the extracellular matrix, a proteolytic enzyme, a lipid, and inflammation, or a combination thereof.
- the additional marker is selected from ETS domain- containing protein Elk-1 (ELK-1), phosphorylated ELK-1 (p-ELK-1), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), D-dimer, prostatic acid phosphatase (PAP), C-reactive protein (CRP), cystatin C, procollagen III N-terminal propeptide (PIIINP), Tissue plasminogen activator (tPA), Paired related homeobox 1 (PRX-1), TNF-related weak inducer of apoptosis (TWEAK), alpha 1 -antitrypsin (al-AT), P-elastase, osteopontin (OPN), and osteoprotegerin (OPG), carboxyterminal propeptide of type I procollagen (PICP), tenascin-C (TN-
- a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection, may further undergo a medical intervention to treat the aneurysm, for example the administration of a suitable compound or composition or a surgical intervention.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering to the subject a compound or composition capable of inhibiting, delaying, or reducing aneurysmal progression or growth, or capable of stabilizing the aneurysm.
- the subject is treated for the aneurysm by undergoing a surgical intervention, for example open surgical or endovascular aneurysm repair.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of a KYNU inhibitor as a monotherapy, or in combination with another agent.
- the KYNU inhibitor is 2-amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid.
- the KYNU inhibitor is dihydro-L-kynurenine.
- the KYNU inhibitor is benserazide.
- the KYNU inhibitor is OMBA.
- the subject is administered a KYNU inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KYNU inhibitor in combination with a TD02 inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with a KMO inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with acipimox. In one embodiment, the subject is administered a KYNU inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KYNU inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with 7-Cl-O-Nec-l .
- the subject is administered a KYNU inhibitor in combination with a ⁇ -blocker. In one embodiment, the subject is administered a KYNU inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KYNU inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in combination with tetracycline/macrolide. In one embodiment, the subject is administered a KYNU inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with losartan.
- ACEI angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor blocker
- the subject is administered a KYNU inhibitor in combination with a statin.
- the subject is administered a KYNU inhibitor in combination
- the subject is administered a KYNU inhibitor in combination with pravastatin. In one embodiment, the subject is administered a KYNU inhibitor in combination with atenolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with perindopril. In one embodiment, the subject is administered a KYNU inhibitor in combination with verapamil. In one embodiment, the subject is administered a KYNU inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KYNU inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KYNU inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with doxycycline.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of a KMO inhibitor as a monotherapy, or in combination with another agent.
- the KMO inhibitor is NBA.
- the KMO inhibitor is GSKl 80.
- the KMO inhibitor is (R)-3-(5-chloro-6-(l-phenylethoxy)benzo[d]isoxazol-3-yl)propanoic acid.
- the KMO inhibitor is CHDI-340246.
- the KMO inhibitor is des-amino FCE 28833.
- the KMO inhibitor is UPF 648. In one embodiment, the KMO inhibitor is Ro-61-8048. In one embodiment, the subject is administered a KMO inhibitor in combination with an IDOl inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a TD02 inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a KYNU inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with acipimox. In one embodiment, the subject is administered a KMO inhibitor in combination with fenofibrate.
- the subject is administered a KMO inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KMO inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KMO inhibitor in combination with a ⁇ -blocker. In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KMO inhibitor in combination with a statin. In one embodiment, the subject is administered a KMO inhibitor in combination with tetracycline/macrolide.
- ACEI angiotensin converting enzyme inhibitor
- ARBs angiotensin II type 1 receptor
- the subject is administered a KMO inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with losartan. In one embodiment, the subject is administered a KMO inhibitor in combination with pravastatin. In one embodiment, the subject is administered a KMO inhibitor in combination with atenolol. In one embodiment, the subject is administered a KMO inhibitor in combination with perindopril. In one embodiment, the subject is administered a KMO inhibitor in combination with verapamil. In one embodiment, the subject is administered a KMO inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KMO inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KMO inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KMO inhibitor in combination with doxycycline.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof either as monotherapy or in combination with another agent.
- the IDOl inhibitor is indoximod.
- the IDOl inhibitor is navoximod.
- the IDOl inhibitor is LG802.
- the IDOl inhibitor is epacadostat.
- the IDOl inhibitor is BMS-986205.
- the IDOl inhibitor is PF-0684003.
- the dual ID01/TD02 inhibitor is HTI-1090. In one embodiment, the dual ID01/TD02 inhibitor is RG-70099. In one embodiment, the IDOl inhibitor is necrostatin-1. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KMO inhibitor In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KYNU inhibitor. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with acipimox.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with fenofibrate. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with telmisartan. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with 7-Cl-O-Nec- 1. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ⁇ -blocker.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI angiotensin converting enzyme inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ARBs angiotensin II type 1 receptor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a statin.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with tetracycline/macrolide. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ERK inhibitor. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with losartan. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with pravastatin.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with atenolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with perindopril. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with verapamil. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with roxithromycin.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with ethinyl estradiol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with nebivolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with doxycycline.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of acipimox as a monotherapy, or in combination with another agent.
- the subject is administered acipimox in combination with a KMO inhibitor.
- the subject is administered acipimox in combination with an IDOl inhibitor.
- the subject is administered acipimox in combination with a TD02 inhibitor.
- the subject is administered acipimox in combination with a dual ID01/TD02 inhibitor.
- the subject is administered acipimox in combination with a KYNU inhibitor. In one embodiment, the subject is administered acipimox in combination with acipimox. In one embodiment, the subject is administered acipimox in combination with fenofibrate. In one embodiment, the subject is administered acipimox in combination with telmisartan. In one embodiment, the subject is administered acipimox in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered acipimox in combination with a ⁇ -blocker. In one embodiment, the subject is administered acipimox in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI an angiotensin converting enzyme inhibitor
- the subject is administered acipimox in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- AGTR1 angiotensin II type 1 receptor
- the subject is administered acipimox in combination with a statin.
- the subject is administered acipimox in combination with tetracycline/macrolide.
- the subject is administered acipimox in combination with a ERK inhibitor.
- the subject is administered acipimox in combination with losartan.
- the subject is administered acipimox in combination with pravastatin.
- the subject is administered acipimox in combination with atenolol.
- the subject is acipimox in combination with perindopril. In one embodiment, the subject is administered acipimox in combination with verapamil. In one embodiment, the subject is administered acipimox in combination with roxithromycin. In one embodiment, the subject is administered acipimox in combination with ethinyl estradiol. In one embodiment, the subject is administered acipimox in combination with nebivolol. In one embodiment, the subject is administered acipimox in combination with doxycycline.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of fenofibrate.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of telmisartan.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of 7-Cl-O-Nec-l .
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of a ⁇ -blocker.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of an angiotensin converting enzyme inhibitor (ACEI).
- ACEI angiotensin converting enzyme inhibitor
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ATR1 angiotensin II type 1 receptor
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of a statin.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of tetracycline/macrolide
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of a ERK inhibitor.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of losartan.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of pravastatin
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of atenolol
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of perindopril.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of verapamil
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of roxithromycin.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of ethinyl estradiol.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection is provided comprising administering an effective amount of nebivolol.
- a method of treating a subject determined to have 3-HAA levels indicative of the formation or expansion of an aneurysm, or whose 3-HAA levels indicate a risk for dissection comprising administering an effective amount of doxy cycline.
- a method of treating a subject having a formed aneurysm comprising administering to the subject an effective amount of a compound described herein.
- a method of treating a subject having a formed aneurysm comprising administering to the subject an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is 2-amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid.
- the KYNU inhibitor is dihydro-L-kynurenine.
- the KYNU inhibitor is benserazide.
- the KYNU inhibitor is OMB A.
- the subject is administered a KYNU inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KYNU inhibitor in combination with a TD02 inhibitor.
- the subject is administered a KYNU inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with a KMO inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with acipimox. In one embodiment, the subject is administered a KYNU inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KYNU inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KYNU inhibitor in combination with a ⁇ -blocker.
- the subject is administered a KYNU inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KYNU inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in combination with tetracycline/macrolide. In one embodiment, the subject is administered a KYNU inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with losartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with pravastatin.
- ACEI an angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor blocker
- the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in
- the subject is administered a KYNU inhibitor in combination with atenolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with perindopril. In one embodiment, the subject is administered a KYNU inhibitor in combination with verapamil. In one embodiment, the subject is administered a KYNU inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KYNU inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KYNU inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with doxycycline. In some embodiments, the aneurysm is an AAA.
- the aneurysm is a TAA. In some embodiments, the aneurysm is a CA. In some embodiments, the subject is at risk for developing a dissected aneurysm, for example a dissected AAA, dissected TAA, or dissected CA. In some embodiments, the subject has an AAA or TAA with an aortic diameter of less than or equal to about 3 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of less than or equal to about 5 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 5 cm.
- the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 7 cm. In some embodiments, the subject has a CA with an arterial diameter of less than or equal to about 5 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 5 mm. In some embodiments, the subj ect has a CA with an arterial diameter of greater than or equal to about 10 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 25 mm.
- a method of treating a subject having a formed aneurysm comprising administering to the subject an effective amount of a KMO inhibitor.
- the KMO inhibitor is NBA.
- the KMO inhibitor is GSK180.
- the KMO inhibitor is (R)-3-(5-chloro-6-(l-phenylethoxy)benzo[d]isoxazol-3- yl)propanoic acid.
- the KMO inhibitor is CHDI-340246.
- the KMO inhibitor is des-amino FCE 28833.
- the KMO inhibitor is UPF 648.
- the KMO inhibitor is Ro-61-8048.
- the subject is administered a KMO inhibitor in combination with an IDOl inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a TD02 inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with a KYNU inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with acipimox. In one embodiment, the subject is administered a KMO inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KMO inhibitor in combination with telmisartan.
- the subject is administered a KMO inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KMO inhibitor in combination with a ⁇ -blocker. In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KMO inhibitor in combination with a statin. In one embodiment, the subject is administered a KMO inhibitor in combination with tetracycline/macrolide. In one embodiment, the subject is administered a KMO inhibitor in combination with a ERK inhibitor.
- ACEI angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor
- the subject is administered a KMO inhibitor in combination with a statin. In one embodiment, the
- the subject is administered a KMO inhibitor in combination with losartan. In one embodiment, the subject is administered a KMO inhibitor in combination with pravastatin. In one embodiment, the subject is administered a KMO inhibitor in combination with atenolol. In one embodiment, the subject is administered a KMO inhibitor in combination with perindopril. In one embodiment, the subject is administered a KMO inhibitor in combination with verapamil. In one embodiment, the subject is administered a KMO inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KMO inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KMO inhibitor in combination with nebivolol.
- the subject is administered a KMO inhibitor in combination with doxycycline.
- the aneurysm is an AAA.
- the aneurysm is a TAA.
- the aneurysm is a CA.
- the subject is at risk for developing a dissected aneurysm, for example a dissected AAA, dissected TAA, or dissected CA.
- the subject has an AAA or TAA with an aortic diameter of less than or equal to about 3 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of less than or equal to about 5 cm.
- the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 5 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 7 cm. In some embodiments, the subject has a CA with an arterial diameter of less than or equal to about 5 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 5 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 10 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 25 mm.
- a method of treating a subject having a formed aneurysm comprising administering an effective amount of an IDOl inhibitor, a TD02 inhibitor, a dual IDO 1/TD02 inhibitor, or a combination thereof either as monotherapy or in combination with another agent.
- the IDOl inhibitor is indoximod.
- the IDOl inhibitor is navoximod.
- the IDOl inhibitor is LG802.
- the IDOl inhibitor is epacadostat.
- the IDOl inhibitor is BMS- 986205.
- the IDOl inhibitor is PF-0684003.
- the dual ID01/TD02 inhibitor is HTI-1090.
- the dual ID01/TD02 inhibitor is RG- 70099.
- the IDOl inhibitor is necrostatin-1.
- the subject is administered an IDOl inhibitor is not necrostatin-1.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KMO inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KYNU inhibitor.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with acipimox.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with fenofibrate. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with telmisartan. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with 7-Cl-O-Nec-l .
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ⁇ -blocker.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI angiotensin converting enzyme inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ATR1 angiotensin II type 1 receptor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a statin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with tetracycline/macrolide. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ERK inhibitor. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with losartan.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with pravastatin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with atenolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with perindopril. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with verapamil.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with roxithromycin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with ethinyl estradiol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with nebivolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with doxycycline.
- a method of treating a subject having a formed aneurysm comprising administering to the subject an effective amount of acipimox.
- the subject is administered acipimox in combination with a KMO inhibitor.
- the subject is administered acipimox in combination with an IDOl inhibitor.
- the subject is administered acipimox in combination with a TD02 inhibitor.
- the subject is administered acipimox in combination with a dual ID01/TD02 inhibitor.
- the subject is administered acipimox in combination with a KYNU inhibitor.
- the subject is administered acipimox in combination with acipimox.
- the subject is administered acipimox in combination with fenofibrate. In one embodiment, the subject is administered acipimox in combination with telmisartan. In one embodiment, the subject is administered acipimox in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered acipimox in combination with a ⁇ -blocker. In one embodiment, the subject is administered acipimox in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered acipimox in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ACEI angiotensin converting enzyme inhibitor
- ARBs angiotensin II type 1 receptor
- the subject is administered acipimox in combination with a statin. In one embodiment, the subject is administered acipimox in combination with tetracycline/macrolide. In one embodiment, the subject is administered acipimox in combination with a ERK inhibitor. In one embodiment, the subject is administered acipimox in combination with losartan. In one embodiment, the subject is administered acipimox in combination with pravastatin. In one embodiment, the subject is administered acipimox in combination with atenolol. In one embodiment, the subject is acipimox in combination with perindopril. In one embodiment, the subject is administered acipimox in combination with verapamil.
- the subject is administered acipimox in combination with roxithromycin. In one embodiment, the subject is administered acipimox in combination with ethinyl estradiol. In one embodiment, the subject is administered acipimox in combination with nebivolol. In one embodiment, the subject is administered acipimox in combination with doxycycline.
- the aneurysm is an AAA. In some embodiments, the aneurysm is a TAA. In some embodiments, the aneurysm is a CA. In some embodiments, the subject is at risk for developing a dissected aneurysm, for example a dissected AAA, dissected TAA, or dissected CA.
- the subject has an AAA or TAA with an aortic diameter of less than or equal to about 3 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of less than or equal to about 5 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 5 cm. In some embodiments, the subject has an AAA or TAA with an aortic diameter of greater than or equal to about 7 cm. In some embodiments, the subject has a CA with an arterial diameter of less than or equal to about 5 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 5 mm. In some embodiments, the subj ect has a CA with an arterial diameter of greater than or equal to about 10 mm. In some embodiments, the subject has a CA with an arterial diameter of greater than or equal to about 25 mm.
- provided herein is a method of prophylactically inhibiting the formation of an aneurysm in a subject predisposed to the development of an aneurysm by administering to the subject a compound described herein.
- a method for the prophylactic inhibition of the formation of an aneurysm in a subject predisposed to the development of an aneurysm comprising administering an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is 2-amino-4-[3'-hydroxyphenyl]-4-hydroxybutanoic acid.
- the KYNU inhibitor is dihydro-L-kynurenine.
- the KYNU inhibitor is benserazide.
- the KYNU inhibitor is OMB A.
- the subject is administered a KYNU inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KYNU inhibitor in combination with a TD02 inhibitor.
- the subject is administered a KYNU inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with a KMO inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with acipimox. In one embodiment, the subject is administered a KYNU inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KYNU inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KYNU inhibitor in combination with a ⁇ -blocker.
- the subject is administered a KYNU inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KYNU inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in combination with tetracycline/macrolide. In one embodiment, the subject is administered a KYNU inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with losartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with pravastatin.
- ACEI an angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor blocker
- the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in
- the subject is administered a KYNU inhibitor in combination with atenolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with perindopril. In one embodiment, the subject is administered a KYNU inhibitor in combination with verapamil. In one embodiment, the subject is administered a KYNU inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KYNU inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KYNU inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with doxycycline. . In one embodiment, the subject is predisposed to development of AAA.
- the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys- Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome. In one embodiment, the disorder is familial thoracic aortic aneurysm/dissection. In one embodiment, the disorder is Shprintzen-Goldberg syndrome. In one embodiment, the disorder is cutis laxa syndrome.
- the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1A1. In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12.
- the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1. In one embodiment, a method for the prophylactic inhibition of the formation of an aneurysm in a subject predisposed to the development of an aneurysm is provided comprising administering an effective amount of a KMO inhibitor. In one embodiment, the KMO inhibitor is NBA. In one embodiment, the KMO inhibitor is GSKl 80.
- the KMO inhibitor is (R)-3-(5-chloro-6-(l-phenylethoxy)benzo[d]isoxazol-3-yl)propanoic acid.
- the KMO inhibitor is CHDI-340246.
- the KMO inhibitor is des-amino FCE 28833.
- the KMO inhibitor is UPF 648.
- the KMO inhibitor is Ro-61-8048.
- the subject is administered a KMO inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KMO inhibitor in combination with a TD02 inhibitor.
- the subject is administered a KMO inhibitor in combination with a dual ID01/TD02 inhibitor.
- the subject is administered a KMO inhibitor in combination with a KYNU inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with acipimox. In one embodiment, the subject is administered a KMO inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KMO inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KMO inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KMO inhibitor in combination with a ⁇ -blocker. In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI an angiotensin converting enzyme inhibitor
- the subject is administered a KMO inhibitor in combination with an angiotensin II type 1 receptor (AGTRl) blocker (ARBs).
- ATRl angiotensin II type 1 receptor
- the subject is administered a KMO inhibitor in combination with a statin.
- the subject is administered a KMO inhibitor in combination with tetracycline/macrolide.
- the subject is administered a KMO inhibitor in combination with a ERK inhibitor.
- the subject is administered a KMO inhibitor in combination with losartan.
- the subject is administered a KMO inhibitor in combination with pravastatin.
- the subject is administered a KMO inhibitor in combination with atenolol.
- the subject is administered a KMO inhibitor in combination with perindopril. In one embodiment, the subject is administered a KMO inhibitor in combination with verapamil. In one embodiment, the subject is administered a KMO inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KMO inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KMO inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KMO inhibitor in combination with doxycycline. In one embodiment, the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome.
- the disorder is Loeys-Dietz syndrome.
- the disorder is aneurysms-osteoarthritis syndrome.
- the disorder is Ehlers-Danlos syndrome.
- the disorder is vascular Ehlers-Danlos syndrome.
- the disorder is familial thoracic aortic aneurysm/dissection.
- the disorder is Shprintzen-Goldberg syndrome.
- the disorder is cutis laxa syndrome.
- the disorder is aortic valve disease.
- the disorder is arterial tortuosity syndrome.
- the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1 Al . In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- a method for the prophylactic inhibition of the formation of an aneurysm in a subject predisposed to the development of an aneurysm comprising administering an effective amount of an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- the IDOl inhibitor is indoximod.
- the IDOl inhibitor is navoximod.
- the IDOl inhibitor is NLG802.
- the IDOl inhibitor is epacadostat.
- the IDOl inhibitor is BMS-986205.
- the IDOl inhibitor is PF-0684003.
- the dual ID01/TD02 inhibitor is HTI-1090.
- the dual ID01/TD02 inhibitor is RG-70099.
- the IDOl inhibitor is necrostatin-1.
- the subject is administered an IDOl inhibitor that is not necrostatin-1.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KMO inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KYNU inhibitor.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with acipimox.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with fenofibrate. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with telmisartan. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with 7-Cl-O-Nec-l .
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ⁇ -blocker.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI angiotensin converting enzyme inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ATR1 angiotensin II type 1 receptor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a statin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with tetracycline/macrolide. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ERK inhibitor. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with losartan.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with pravastatin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with atenolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with perindopril. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with verapamil.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with roxithromycin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with ethinyl estradiol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with nebivolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with doxycycline.
- the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys-Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome. In one embodiment, the disorder is familial thoracic aortic aneurysm/dis section. In one embodiment, the disorder is Shprintzen-Goldberg syndrome.
- the disorder is cutis laxa syndrome. In one embodiment, the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1A1. In one embodiment, the disorder is a mutation in the gene COL1 A2.
- the disorder is a mutation in the gene MED12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1. In one embodiment, a method for the prophylactic inhibition of the formation of an aneurysm in a subject predisposed to the development of an aneurysm is provided comprising administering an effective amount of acipimox. In one embodiment, the subject is administered acipimox in combination with a KMO inhibitor.
- the subject is administered acipimox in combination with an IDOl inhibitor. In one embodiment, the subject is administered acipimox in combination with a TD02 inhibitor. In one embodiment, the subject is administered acipimox in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered acipimox in combination with a KYNU inhibitor. In one embodiment, the subject is administered acipimox in combination with acipimox. In one embodiment, the subject is administered acipimox in combination with fenofibrate. In one embodiment, the subject is administered acipimox in combination with telmisartan.
- the subject is administered acipimox in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered acipimox in combination with a ⁇ -blocker. In one embodiment, the subject is administered acipimox in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered acipimox in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered acipimox in combination with a statin. In one embodiment, the subject is administered acipimox in combination with tetracycline/macrolide.
- ACEI angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor
- the subject is administered acipimox in combination with a statin. In one embodiment, the subject is administered acipimox in combination with tetra
- the subject is administered acipimox in combination with a ERK inhibitor. In one embodiment, the subject is administered acipimox in combination with losartan. In one embodiment, the subject is administered acipimox in combination with pravastatin. In one embodiment, the subject is administered acipimox in combination with atenolol. In one embodiment, the subject is acipimox in combination with perindopril. In one embodiment, the subject is administered acipimox in combination with verapamil. In one embodiment, the subject is administered acipimox in combination with roxithromycin. In one embodiment, the subject is administered acipimox in combination with ethinyl estradiol.
- the subject is administered acipimox in combination with nebivolol. In one embodiment, the subject is administered acipimox in combination with doxycycline. In one embodiment, the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA. In one embodiment, the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys- Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome.
- the disorder is familial thoracic aortic aneurysm/dissection. In one embodiment, the disorder is Shprintzen-Goldberg syndrome. In one embodiment, the disorder is cutis laxa syndrome. In one embodiment, the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation.
- the disorder is a mutation in the gene COL1A1. In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- provided herein is a method of reducing the risk of aneurysmal rupture in a subject predisposed to the development of an aneurysm by administering to the subject a compound described herein.
- a method for reducing the risk of aneurysmal rupture in a subject predisposed to the development of an aneurysm comprising administering an effective amount of a KYNU inhibitor.
- the KYNU inhibitor is 2-amino-4-[3'- hydroxyphenyl]-4-hydroxybutanoic acid.
- the KYNU inhibitor is dihydro-L- kynurenine.
- the KYNU inhibitor is benserazide.
- the KYNU inhibitor is OMB A.
- the subject is administered a KYNU inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KYNU inhibitor in combination with a TD02 inhibitor.
- the subject is administered a KYNU inhibitor in combination with a dual ID01/TD02 inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with a KMO inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with acipimox. In one embodiment, the subject is administered a KYNU inhibitor in combination with fenofibrate. In one embodiment, the subject is administered a KYNU inhibitor in combination with telmisartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with 7-Cl-O- Nec-1. In one embodiment, the subject is administered a KYNU inhibitor in combination with a ⁇ -blocker.
- the subject is administered a KYNU inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KYNU inhibitor in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs). In one embodiment, the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in combination with tetracycline/macrolide. In one embodiment, the subject is administered a KYNU inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KYNU inhibitor in combination with losartan. In one embodiment, the subject is administered a KYNU inhibitor in combination with pravastatin.
- ACEI an angiotensin converting enzyme inhibitor
- AGTR1 angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor blocker
- the subject is administered a KYNU inhibitor in combination with a statin. In one embodiment, the subject is administered a KYNU inhibitor in
- the subject is administered a KYNU inhibitor in combination with atenolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with perindopril. In one embodiment, the subject is administered a KYNU inhibitor in combination with verapamil. In one embodiment, the subject is administered a KYNU inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KYNU inhibitor in combination with ethinyl estradiol. In one embodiment, the subject is administered a KYNU inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KYNU inhibitor in combination with doxycycline. . In one embodiment, the subject is predisposed to development of AAA.
- the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys-Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome. In one embodiment, the disorder is familial thoracic aortic aneurysm/dissection. In one embodiment, the disorder is Shprintzen-Goldberg syndrome. In one embodiment, the disorder is cutis laxa syndrome.
- the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1 Al . In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12.
- the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- a method for reducing the risk of aneurysmal rupture in a subject predisposed to the development of an aneurysm comprising administering an effective amount of a KMO inhibitor.
- the KMO inhibitor is NBA.
- the KMO inhibitor is GSK180.
- the KMO inhibitor is (R)-3-(5-chloro-6-(l- phenylethoxy)benzo[d]isoxazol-3-yl)propanoic acid.
- the KMO inhibitor is CHDI-340246.
- the KMO inhibitor is des-amino FCE 28833.
- the KMO inhibitor is UPF 648.
- the KMO inhibitor is Ro-61- 8048.
- the subject is administered a KMO inhibitor in combination with an IDOl inhibitor.
- the subject is administered a KMO inhibitor in combination with a TD02 inhibitor.
- the subject is administered a KMO inhibitor in combination with a dual ID01/TD02 inhibitor.
- the subject is administered a KMO inhibitor in combination with a KYNU inhibitor.
- the subject is administered a KMO inhibitor in combination with acipimox.
- the subject is administered a KMO inhibitor in combination with fenofibrate.
- the subject is administered a KMO inhibitor in combination with telmisartan.
- the subject is administered a KMO inhibitor in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered a KMO inhibitor in combination with a ⁇ -blocker. In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin converting enzyme inhibitor (ACEI). In one embodiment, the subject is administered a KMO inhibitor in combination with an angiotensin II type 1 receptor (AGTRl) blocker (ARBs). In one embodiment, the subject is administered a KMO inhibitor in combination with a statin. In one embodiment, the subject is administered a KMO inhibitor in combination with tetracycline/macrolide.
- ACEI angiotensin converting enzyme inhibitor
- AGTRl angiotensin II type 1 receptor
- ARBs angiotensin II type 1 receptor
- the subject is administered a KMO inhibitor in combination with a statin. In one embodiment, the subject is administered a KMO inhibitor in combination with tetracycline/macrolide.
- the subject is administered a KMO inhibitor in combination with a ERK inhibitor. In one embodiment, the subject is administered a KMO inhibitor in combination with losartan. In one embodiment, the subject is administered a KMO inhibitor in combination with pravastatin. In one embodiment, the subject is administered a KMO inhibitor in combination with atenolol. In one embodiment, the subject is administered a KMO inhibitor in combination with perindopril. In one embodiment, the subject is administered a KMO inhibitor in combination with verapamil. In one embodiment, the subject is administered a KMO inhibitor in combination with roxithromycin. In one embodiment, the subject is administered a KMO inhibitor in combination with ethinyl estradiol.
- the subject is administered a KMO inhibitor in combination with nebivolol. In one embodiment, the subject is administered a KMO inhibitor in combination with doxycycline. In one embodiment, the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA. In one embodiment, the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys- Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome.
- the disorder is familial thoracic aortic aneurysm/dissection. In one embodiment, the disorder is Shprintzen-Goldberg syndrome. In one embodiment, the disorder is cutis laxa syndrome. In one embodiment, the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation.
- the disorder is a mutation in the gene COL1A1. In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- a method for reducing the risk of aneurysmal rupture in a subject predisposed to the development of an aneurysm comprising administering an effective amount of an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof.
- the IDOl inhibitor is indoximod.
- the IDOl inhibitor is navoximod.
- the IDOl inhibitor is LG802.
- the IDOl inhibitor is epacadostat.
- the IDOl inhibitor is BMS-986205.
- the IDOl inhibitor is PF-0684003.
- the dual ID01/TD02 inhibitor is HTI-1090.
- the dual ID01/TD02 inhibitor is RG-70099.
- the IDOl inhibitor is necrostatin-1.
- the subject is administered an IDOl inhibitor that is not necrostatin-1.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KMO inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a KYNU inhibitor.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with acipimox.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with fenofibrate. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with telmisartan. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with 7-Cl-O-Nec-l .
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ⁇ -blocker.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI angiotensin converting enzyme inhibitor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- ATR1 angiotensin II type 1 receptor
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a statin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with tetracycline/macrolide. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with a ERK inhibitor. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with losartan.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with pravastatin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with atenolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with perindopril. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with verapamil.
- the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with roxithromycin. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with ethinyl estradiol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with nebivolol. In one embodiment, the subject is administered an IDOl inhibitor, a TD02 inhibitor, a dual ID01/TD02 inhibitor, or a combination thereof in combination with doxycycline.
- the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome. In one embodiment, the disorder is Loeys- Dietz syndrome. In one embodiment, the disorder is aneurysms-osteoarthritis syndrome. In one embodiment, the disorder is Ehlers-Danlos syndrome. In one embodiment, the disorder is vascular Ehlers-Danlos syndrome. In one embodiment, the disorder is familial thoracic aortic aneurysm/dissection. In one embodiment, the disorder is Shprintzen-Goldberg syndrome.
- the disorder is cutis laxa syndrome. In one embodiment, the disorder is aortic valve disease. In one embodiment, the disorder is arterial tortuosity syndrome. In one embodiment, the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1A1. In one embodiment, the disorder is a mutation in the gene COL1A2.
- the disorder is a mutation in the gene MED 12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- a method for reducing the risk of aneurysmal rupture in a subject predisposed to the development of an aneurysm comprising administering an effective amount of acipimox.
- the subject is administered acipimox in combination with a KMO inhibitor.
- the subject is administered acipimox in combination with an IDOl inhibitor.
- the subject is administered acipimox in combination with a TD02 inhibitor.
- the subject is administered acipimox in combination with a dual ID01/TD02 inhibitor.
- the subject is administered acipimox in combination with a KYNU inhibitor.
- the subject is administered acipimox in combination with acipimox. In one embodiment, the subject is administered acipimox in combination with fenofibrate. In one embodiment, the subject is administered acipimox in combination with telmisartan. In one embodiment, the subject is administered acipimox in combination with 7-Cl-O-Nec-l . In one embodiment, the subject is administered acipimox in combination with a ⁇ -blocker. In one embodiment, the subject is administered acipimox in combination with an angiotensin converting enzyme inhibitor (ACEI).
- ACEI an angiotensin converting enzyme inhibitor
- the subject is administered acipimox in combination with an angiotensin II type 1 receptor (AGTR1) blocker (ARBs).
- AGTR1 angiotensin II type 1 receptor
- the subject is administered acipimox in combination with a statin.
- the subject is administered acipimox in combination with tetracycline/macrolide.
- the subject is administered acipimox in combination with a ERK inhibitor.
- the subject is administered acipimox in combination with losartan.
- the subject is administered acipimox in combination with pravastatin.
- the subject is administered acipimox in combination with atenolol.
- the subject is acipimox in combination with perindopril. In one embodiment, the subject is administered acipimox in combination with verapamil. In one embodiment, the subject is administered acipimox in combination with roxithromycin. In one embodiment, the subject is administered acipimox in combination with ethinyl estradiol. In one embodiment, the subject is administered acipimox in combination with nebivolol. In one embodiment, the subject is administered acipimox in combination with doxycycline. In one embodiment, the subject is predisposed to development of AAA. In one embodiment, the subject is predisposed to development of TAA. In one embodiment, the subject is predisposed to development of CA.
- the genetic disorder is Marfan syndrome, or a disorder related to Marfan syndrome.
- the disorder is Loeys-Dietz syndrome.
- the disorder is aneurysms-osteoarthritis syndrome.
- the disorder is Ehlers-Danlos syndrome.
- the disorder is vascular Ehlers-Danlos syndrome.
- the disorder is familial thoracic aortic aneurysm/dissection.
- the disorder is Shprintzen-Goldberg syndrome.
- the disorder is cutis laxa syndrome.
- the disorder is aortic valve disease.
- the disorder is arterial tortuosity syndrome.
- the disorder is X-linked Alport syndrome. In one embodiment, the disorder is Turner syndrome. In one embodiment, the disorder is Mitral valve, myopia, Aorta, Skin and Skeletal (MASS) syndrome. In one embodiment, the disorder is Beals syndrome. In one embodiment, the disorder is Bicuspid Aortic Valve syndrome. In one embodiment, the disorder is a congenital heart malformation. In one embodiment, the disorder is a mutation in the gene COL1 Al . In one embodiment, the disorder is a mutation in the gene COL1A2. In one embodiment, the disorder is a mutation in the gene MED 12. In one embodiment, the disorder is a mutation in the gene, SMAD4. In one embodiment, the disorder is a mutation in the gene PLOD3. In one embodiment, the disorder is a mutation in the gene ENG. In one embodiment, the disorder is a mutation in the gene ACVRL1. In one embodiment, the disorder is a mutation in the gene NF 1.
- Antibodies to MMP2 (ab37150) and alpha smooth muscle Actin (ab5694) were from Abeam.
- An antibody against IFN-y (AMC4834) was from lnvitrogen.
- Antibodies to phospho- Elkl (Ser383, 9181), Elkl (9182), and all secondary antibodies were from Cell Signaling Technology.
- Antibodies to human kynureninase (sc-390360), J3-actin (sc-47778) and GAPDH (sc-166545) were from Santa Cruz Biotechnology.
- An antibody to locate 100 (MAB5412) was from Millipore.
- An antibody against mouse kynureninase (MAB7389) was from R&D System.
- a goat anti-mouse lgG conjugated to Alexa488 green (A-l 1001) was purchased from lnvitrogen. All primary antibodies were used in a 1 : 1,000 dilution for Western blot and a 1 : 100 dilution for immunocytochemistry and immunohistochemistry.
- IFN-y Recombinant Human Protein (PHC4031) was obtained from GIBCO.
- Recombinant human pro-MMP2 protein (PF037) was purchased from Millipore.
- 3 -Hydroxy -DL-kynurenine (H1771), anthranilic acid (A89855), and Angiotensin II (Ang II, A9525) were from Sigma.
- Kynurenic acid (sc-202683), Xanthurenic acid (sc-258335), and Quinolinic acid (sc-203226) were purchased from Santa Cruz Biotechnology.
- Control siRNA (sc-37007) and siRNAs targeting 100 (sc-45939), kynureninase (sc-95023) were from Santa Cruz Biotechnology.
- the transfection reagents for siRNA (Lipofectamine RNAiMax, 13778150) were from lnvitrogen.
- IDO _/" and ApoE _/” mice were obtained from Jackson laboratory (Bar Harbor, Maine) in a C57BL/6 background. IDO _/" mice were crossed with ApoE _/” mice to generate ApoE ⁇ VIDO " " mice. Mice were housed in temperature-controlled cages under a 12-hour light/dark cycle and given free access to water and normal chow. All procedures involving animals were approved by the Institutional Animal Care and Use Committee at the University of Oklahoma Health Sciences Center.
- mice at age 8 weeks or 4 weeks after bone marrow transplantation on a chow diet were infused with Angll (1,000 ng/kg/min) or physiological saline (0.9% sodium chloride) by Alzet osmotic pumps (OURECT Corp, Model 2004) as described previously in Wang et al., Activation of NAD(P)H Oxidase by Tryptophan-Derived 3- Hydroxykynurenine Accelerates Endothelial Apoptosis and Dysfunction In Vivo. Circ Res. (2014) 114:480-92.
- ApoE “/_ and ApoE ⁇ VIDO " mice at age 8 weeks on a chow diet were intraperitoneally injected with 3-HAA (200 mg/kg. d) or vehicle for 6 weeks.
- 3-HAA was dissolved in OMSO and further diluted in Captisol (Captisol Technology).
- the Ambion® in vivo pre-designed siRNA delivery was carried out according to lnvitrogen's in vivo RNAi protocol.
- 0.875 mg/ml complex of control siRNA (lnvitrogen, 4457289) or kynureninase siRNA (lnvitrogen, 4457308) with lnvivofectamine® 2.0 Reagent (lnvitrogen, 1377-505) were Prepared in PBS using a Float-A-Lyzer® G2 cassette (Spectrum labs, G235031) freshly before every injection.
- 200 ⁇ of siRNA (7 mg/Kg) complex was delivered into an ApoE " mouse by tail vein injection every five days which started on the first day of Angll infusion.
- Bone marrow transplantation was performed as described previously (Lukasova M, et al., Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest. (2011) 121 : 1163-73; Duran-Struuck R and Dysko RC. Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies. J Am Assoc Lab Anim Sci. (2009) 48: 11-22). Bone marrow was obtained aseptically from femora and tibiae of ApoE _/" or ApoE ⁇ VIDO " " mice.
- aneurysm incidence based on a definition of aneurysm as an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice, as described previously (Sparks AR, et al., Imaging of abdominal aortic aneurysms. Am Fam Physician. (2002) 65: 1565-70).
- the average diameter of the normal suprarenal aorta in control mice is 0.8 mm.
- mice were killed.
- aortas were perfused with saline and fixed with 10% formalin in PBS for 5 minutes.
- Whole aortas were harvested, fixed and embedded in paraffin, and cross-sections (5 ⁇ ) were prepared. Paraffin sections were stained with H&E (IHC World, IW-3100), Van Giesen elastic stain (Sigma, HT25A), Masson tri chrome stain (Sigma, HT15), or were used for immunostaining (DAKO, K4065).
- H&E IHC World, IW-3100
- Van Giesen elastic stain Sigma, HT25A
- Masson tri chrome stain Sigma, HT15
- DAKO immunostaining
- elastin degradation In terms of the determination of elastin degradation, we used a standard for the grades of elastin degradation, as described previously in Satoh K, et al., Cyclophilin A enhances vascular oxidative stress and the development of angiotensin Il-induced aortic aneurysms. Nat Med. (2009) 15:649-56.
- the grades were defined as follows: grade 1, no degradation; grade 2, mild elastin degradation; grade 3, severe elastin degradation; and grade 4, aortic rupture.
- HASMC Human aortic smooth muscle cells
- GASMC Human aortic smooth muscle cells
- GBeCO Human aortic smooth muscle cells
- FBS fetal bovine serum
- penicillin 100 U/ml
- streptomycin 100 ⁇ g/ml
- Smooth Muscle Growth Supplement Gibco, S00725
- Kyn and Trp were measured by HPLC as described previously in Wang Q, et al., Activation of NAD(P)H Oxidase by Tryptophan-Derived 3 -Hydroxy kynurenine Accelerates Endothelial Apoptosis and Dysfunction In Vivo. Circ Res. (2014) 114:480-92.
- Kyn content was estimated along with standards ranging from 0.5-20 ⁇ L-kynurenine (Sigma, K8625), and Trp level was assessed along standards ranging from 1-25 ⁇ DL-Tryptophan (Sigma, 162698), using a GraceVydac C18 column (250x4.6 mm, 5.0 ⁇ ).
- the flow rate was 1 ml/min.
- the column effluent was monitored at 360 nm (Kyn) and 280 nm (Trp) by a UV detector.
- Angll-induced mouse AAA formation in the atherosclerotic-susceptible strain has become the most widely used model. See Qin Z, et al., Angiotensin Il-induced TLR4 mediated abdominal aortic aneurysm in apo lipoprotein E knockout mice is dependent on STAT3. J Mol Cell Cardiol. (2015) 87:160-70; Rateri DL, et al., Prolonged infusion of angiotensin II in ApoE (-/-) mice promotes macrophage recruitment with continued expansion of abdominal aortic aneurysm. Am J Pathol.
- Table 1 Blood pressure and heart rate Angll-infused mice.
- N 6 - 10 in each group. Data are expressed by mean + s.e.m.
- Table 2 Serum lipid and glucose level in Angll-infused mice.
- N 6 -10 in each group. Data are expressed by mean + s.e.m.
- Angll infusion is intensely associated with vascular inflammation, which is considered a key mediator of Angll-induced AAA formation.
- Qin Z et al.
- Angiotensin Il-induced TLR4 mediated abdominal aortic aneurysm in apolipoprotein E knockout mice is dependent on STAT3.
- Owens AP et al.
- MyD88 deficiency attenuates angiotensin Il-induced abdominal aortic aneurysm formation independent of signaling through Toll-like receptors 2 and 4.
- Arterioscler Thromb Vase Biol. (201 1) 31 :2813-9.
- N 6 -10 in each group. Data are expressed by mean + s.e.m.
- MMPs play a key role in the initiation and progression of AAA. See Hellenthal FA, et al, Biomarkers of AAA progression. Part 1 : extracellular matrix degeneration. Nature reviews Cardiology. (2009) 6:464-74.
- VSMC-derived MMP2 Airhart N, et al., Smooth muscle cells from abdominal aortic aneurysms are unique and can independently and synergistically degrade insoluble elastin. J Vase Surg. (2014) 60:1033-41; discussion 1041-2; Dilme IF, et al, Influence of cardiovascular risk factors on levels of matrix metalloproteinases 2 and 9 in human abdominal aortic aneurysms.
- Trp depletion has been shown to inhibit MMP expression in human fibroblasts (Varga J, et al., Control of extracellular matrix degradation by interferon-gamma. The tryptophan connection. Adv Exp Med Biol. (1996) 398: 143-8) and to halt cell cycle progression in T cells (Munn DH, et al, Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. (1999) 189: 1-363-72).
- Hypertryptophanemia (Martin JR., et al., Familial hypertryptophanemia in two siblings. Clin Genet. (1995) 47: 180: Andrade VS, et al., Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats. Molecular and cellular biochemistry. (2012) 362:225-32) is a rare autosomal recessive metabolic disorder that results in a massive buildup of Trp in the blood (Becerra A, et al., Increased activity of indoleamine 2,3- dioxygenase in serum from acutely infected dengue patients linked to gamma interferon antiviral function. J Gen Virol.
- MMP2 were detected in HASMCs incubated with major exogenous metabolites (Wang Q, et al., Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Frontiers in bioscience (Landmark edition). (2015) 20: 1 1 16-43; iank C, et al., Psychological stress-induced, IDOl -dependent tryptophan catabolism: implications on immunosuppression in mice and humans. PLoS One. (2010) 5: el 182) of Trp degradation.
- kynurenic acid (KA) (Klein C, et al., The neuroprotector kynurenic acid increases neuronal cell survival through neprilysin induction. Neuropharmacology. (2013) 70:254-60), AA (Terness P, et al., Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase- expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med.
- xanthurenic acid (Malina HZ, et al., Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown. BMC Physiol. (2001) 1 :7), or quinolinic acid (QA) (Hayashi T, et al., 3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc Natl Acad Sci U S A. (2007) 104:18619-24) ( Figure 5A).
- Kyn can be further metabolized by kynurenine-3-monooxygenase into 3-HK, which is catabolized by KNU to form 3-HAA (Wang Q, et al., Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation.
- Table 4 Serum lipid and glucose level in 3- HAA-injected mice.
- N 6 -10 in each group. Data are expressed by mean ⁇ s.e.m.
- Angll-infused ApoE 7" mice were treated with KNU siRNA. There were no differences in blood pressure or heart rate between scrambled siRNA- and KNU siRNA-transfected, Angll-infused mice (data not shown). Changes in metabolic parameters were also not observed (data not shown). Only 22% of Angll-infused, KNU siRNA-transfected ApoE 7" mice developed AAA compared with a 75% incidence of AAA in Angll-infused, scrambled siRNA-transfected ApoE 7" mice ( Figures 7A and 7B).
- KNU silencing did not alter serum concentrations of inflammatory cytokines in Angll- infused ApoE 7" mice (data not shown). Accordingly, both IFN- ⁇ and IDO expression levels were markedly enhanced in the aortas of Angll-treated ApoE 7" mice with or without KNU knockdown ( Figures 8A, 8B, and 8G). As expected, Angll only increased KNU expression in ApoE 7" mice ( Figures 8A, 8B, and 8G).
- Example 12 Effect of Acipimox on preventing Angll-induced abdominal aortic aneurysm
- mice at age eight weeks were administrated either 1) acipimox (0.1% wt) or 2) vehicle control (water) by drinking water.
- Alzet osmotic mini pumps (Model 2004) were implanted into each group. Pumps were filled either with 1) saline vehicle or 2) solutions of Ang II (Sigma Chemical Co., St. Louis, Missouri, USA) that delivered (subcutaneously) 1.44mg/kg/day of Ang II for 28 days. Pumps were placed into the subcutaneous space of isoflurane anesthetized mice through a small incision in the back of the neck that was closed with surgical glue. All incision sites healed rapidly without the need for any medication.
- aneurysm incidence was quantified based on a definition of aneurysm as an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice.
- the average diameter of the normal suprarenal aorta in control mice is 0.8 mm. Therefore, a threshold of 1.22 mm as evidence of aneurysm formation was set.
- Abdominal aorta dimeter was measured by ultrasound as described above. As shown in Figures 21, 22A and 22B, acipimox treatment inhibited Angll-induced abdominal aorta dilation, while Angll significantly increase the diastolic diameter and systolic diameter compared with vehicle and acipimox treated mice.
- Example 13 Effect of Acipimox on treating Ang-II-induced abdominal aortic aneurysm
- mice at age 8 weeks were infused with Angll (1 ,000 ng/kg/rnin) or saline (0.9% sodium chloride) by Alzet osmotic pumps for four weeks.
- mice were treated with acipimox (0.1% wt) or vehicle control (water) by drinking water for 6 weeks.
- AAA incidence maximal abdominal aorta diameter and aorta/body weight ratio were examined to evaluate the therapeutic effect of acipimox on AngTT-indnr.ed AAA.
- AAA incidence was quantified based on a definition of aneurysm as an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice.
- the average diameter of the normal suprarenal aorta in control mice is 0.8 mm. Therefore, a threshold of 1.22 mm as evidence of aneurysm formation was set.
- Vehicle control mice did not develop AAA.
- 3-HAA levels in aneurysm-positive mice are typically between 120- 300 nM, while the range in aneurysm- free mice is 70-100 nM.
- Example 15 Effect of OMBA, NBA, and IMT on Treating AngH-Induced Abdominal Aortic Aneurysm
- mice at age 8 weeks were infused with Angll (1,000 ng/kg/min) or saline (0.9% sodium chloride) by Alzet osmotic pumps for four weeks.
- Ang-II treated mice were divided into five groups of 18 and administered o- methoxybenzoylalanine (OMB), (m-nitrobenzoyl)alanine (NBA), 1 -methyltryptophan (IMT) or vehicle control (water) by drinking water for 6 weeks.
- OMB o- methoxybenzoylalanine
- NBA m-nitrobenzoyl
- IMT 1 -methyltryptophan
- aneurysm incidence was quantified based on a definition of aneurysm as an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice.
- the average diameter of the normal suprarenal aorta in control mice is 0.8 mm. Therefore, a threshold of 1.22 mm as evidence of aneurysm formation was set.
- Vehicle control mice did not develop AAA. Representative aortas from all groups are shown in Figure 30. Incidence of AAA among the various groups of mice is outlined in Figure 31 A and Table 5 below.
- Example 16 Effect of Acipimox on preventing Ang-II-induced abdominal aortic aneurysm in aged mice
- mice in the aged mice group were treated with acipimox (0.1% wt) or vehicle control (water) by drinking water for 6 weeks.
- mice in both age groups were infused with Angll (1,000 ng/kg/min) or saline (0.9% sodium chloride) by Alzet osmotic pumps for four weeks.
- AAA incidence and maximal abdominal aorta diameter were examined to evaluate the therapeutic effect of acipimox on Angll- induced AAA in old mice.
- aneurysm incidence was quantified based on a definition of aneurysm as an external width of the suprarenal aorta that was increased by 50% or greater compared with aortas from saline-infused mice.
- the average diameter of the normal suprarenal aorta in control mice is 0.705 mm. Therefore, a threshold of 1.06 mm as evidence of aneurysm formation was set. Young vehicle control mice did not develop AAA, while the AA incidence was 20% in old mice.
- the AAA incidence was 20% and 70% in young and old mice, respectively.
- acipimox AAA incidence decreased to 25% in the old mice group.
- Representative aortic dissections among the various treatment groups can be found in Figure 36 A. The treatment results are shown in Figure 36B and 36C.
- Example 17 Acipimox inhibits the AngH-induced kynurenine pathway in the abdominal aorta
- mice Male ApoE 7" mice at age 8 weeks were infused with Angll (1,000 ng/kg/min) or saline '(0.9% sodium chloride) by Alzet osmotic pumps for four weeks. Four weeks later, mice were treated with acipimox (0.1 % wt) or vehicle control (water) by drinking water for 6 weeks. Aortic sections of the sacrificed mice were stained using immunohistochemistry to determine levels of KYNU and IDO. The results are shown in Figures 37A-37D.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention concerne des procédés de détection et/ou de traitement d'un sujet présentant un anévrisme ou risquant de développer un anévrisme. Il a été découvert qu'un métabolite clé de la voie de la kynurénine (Kyn), une voie majeure pour le métabolisme de l'acide aminé essentiel tryptophane (Trp) en nicotinamide adénine dinucléotide (NAD +), joue un rôle critique dans la formation des anévrismes, par exemple des anévrismes aortiques abdominaux. En particulier, il a été découvert que l'acide 3-hydroxyanthranilique (3-HAA), un produit de la kynuréninase (KYNU), joue un rôle causal dans la formation d'anévrismes, par exemple, en exerçant des effets pro-inflammatoires sur des cellules de muscle lisse vasculaire. Il a en outre été découvert que des teneurs élevées en 3-HAA sont indicatives de la présence et/ou de l'évolution d'un anévrisme, et que les teneurs en 3-HAA sont corrélées à la taille (diamètre aortique) de l'anévrisme.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/723,304 US11376248B2 (en) | 2017-06-30 | 2019-12-20 | Treatment of aneurysms |
US17/810,620 US20230143415A1 (en) | 2017-06-30 | 2022-07-04 | Treatment of aneurysms |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762527419P | 2017-06-30 | 2017-06-30 | |
US62/527,419 | 2017-06-30 | ||
US201862621169P | 2018-01-24 | 2018-01-24 | |
US62/621,169 | 2018-01-24 | ||
US201862680488P | 2018-06-04 | 2018-06-04 | |
US62/680,488 | 2018-06-04 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/723,304 Continuation US11376248B2 (en) | 2017-06-30 | 2019-12-20 | Treatment of aneurysms |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019006384A1 true WO2019006384A1 (fr) | 2019-01-03 |
Family
ID=64742226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2018/040422 WO2019006384A1 (fr) | 2017-06-30 | 2018-06-29 | Traitement des anévrismes |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2019006384A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020247453A1 (fr) * | 2019-06-06 | 2020-12-10 | The Regents Of The University Of California | Traitement d'anévrismes aortiques |
CN113430229A (zh) * | 2021-06-23 | 2021-09-24 | 温州医科大学 | 一种人源bav-taa疾病多能干细胞模型的构建方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6569190B2 (en) * | 2000-10-11 | 2003-05-27 | Micro Therapeutics, Inc. | Methods for treating aneurysms |
US20140296567A1 (en) * | 2011-07-29 | 2014-10-02 | Göran K. Hansson | 3-hydroxyanthranilic acid (3-haa) therapy for prevention and treatment of hyperlipidemia and its cardiovasular complications |
-
2018
- 2018-06-29 WO PCT/US2018/040422 patent/WO2019006384A1/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6569190B2 (en) * | 2000-10-11 | 2003-05-27 | Micro Therapeutics, Inc. | Methods for treating aneurysms |
US20140296567A1 (en) * | 2011-07-29 | 2014-10-02 | Göran K. Hansson | 3-hydroxyanthranilic acid (3-haa) therapy for prevention and treatment of hyperlipidemia and its cardiovasular complications |
Non-Patent Citations (1)
Title |
---|
SONG ET AL.: "Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases", CELLULAR AND MOLECULAR LIFE SCIENCES, vol. 74, 17 March 2017 (2017-03-17), pages 2899 - 2916, XP036272290 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020247453A1 (fr) * | 2019-06-06 | 2020-12-10 | The Regents Of The University Of California | Traitement d'anévrismes aortiques |
CN113430229A (zh) * | 2021-06-23 | 2021-09-24 | 温州医科大学 | 一种人源bav-taa疾病多能干细胞模型的构建方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Pei et al. | Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model | |
Chen et al. | BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection | |
Navarrete et al. | Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy | |
Billings IV et al. | Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response | |
Stallons et al. | Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis | |
Palm et al. | Renal oxidative stress, oxygenation, and hypertension | |
Zhao et al. | Flavonoid VI-16 protects against DSS-induced colitis by inhibiting Txnip-dependent NLRP3 inflammasome activation in macrophages via reducing oxidative stress | |
Zhao et al. | The interaction between oxidative stress and mast cell activation plays a role in acute lung injuries induced by intestinal ischemia–reperfusion | |
US9730922B2 (en) | Combined therapy for cystic fibrosis | |
Yang et al. | Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells | |
Vinh et al. | Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice | |
EP3427061B1 (fr) | Verwendung von selektive inos-inhibitoren zur behandlung von thorakales aortenaneurysma | |
JP6822412B2 (ja) | 妊娠高血圧腎症のための診断アッセイ及び治療 | |
WO2021146258A1 (fr) | Polythérapie contre le cancer | |
Ding et al. | Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation | |
Wang et al. | HSP27 regulates TGF-β mediated lung fibroblast differentiation through the Smad3 and ERK pathways | |
US10500178B2 (en) | LTB4 inhibition to prevent and treat human lymphedema | |
Bais et al. | Drugs in clinical development to treat autosomal dominant polycystic kidney disease | |
WO2019006384A1 (fr) | Traitement des anévrismes | |
Cowell et al. | Identification of novel targets for PGC-1α and histone deacetylase inhibitors in neuroblastoma cells | |
Liu et al. | Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/TXNIP/NLRP3 signaling pathway | |
Qian et al. | G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE−/− mice | |
ES2395002T3 (es) | Nueva combinación para uso en el tratamiento de trastornos inflamatorios | |
US11376248B2 (en) | Treatment of aneurysms | |
Nasr et al. | Comparable renovascular protective effects of moxonidine and simvastatin in rats exposed to cigarette smoke |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18824610 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18824610 Country of ref document: EP Kind code of ref document: A1 |